Methods and compositions for treatment of presbyopia, mydriasis, and other ocular disorders

ABSTRACT

The invention provides methods, compositions, and kits containing an alpha-adrenergic antagonist, such as phentolamine, for use in monotherapy or as part of a combination therapy to treat patients suffering from presbyopia, mydriasis, and/or other ocular disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international patent applicationno. PCT/US2019/058182, filed Oct. 25, 2019, which claims the benefit ofand priority to U.S. Provisional Patent Application Ser. No. 62/751,391,filed Oct. 26, 2018; the contents of each of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention provides methods, compositions, and kits containing analpha-adrenergic antagonist, such as phentolamine, for use inmonotherapy or as part of a combination therapy to treat patientssuffering from presbyopia, mydriasis, and/or other ocular disorders.

BACKGROUND

Presbyopia is a disorder of the eye associated with aging that resultsin the inability to focus on nearby objects. Presbyopia is generallycaused by a hardening of the eye's lens, which reduces its ability toflex. People often first notice the effects of presbyopia around 40years of age, with the effects becoming increasingly more pronouncedover the following two decades. The effects of presbyopia can have asignificant negative impact on quality of life, for example, interferingwith activities involving reading.

Existing treatments for presbyopia are not effective for all patientsand/or have undesirable characteristics. A common treatment forpresbyopia is the use of corrective lenses (for example, reading glassesor bifocals), which must then be carried by the patient. Additionally,bifocal or multifocal lenses, including contact lenses, can be difficultto use, particularly when undertaking tasks requiring frequent changesbetween viewing near and far objects. Monovision treatment approaches,where one eye is optimized for distance vision and lenses or surgicalmethods compensate for presbyopia in the other eye, result in impaireddepth perception and can be disorienting. Surgical approaches, such asLASIK and corneal inlays, also present all the risks inherent tosurgical procedures. Despite ongoing research, there are currently nonon-invasive, pharmacological treatments for presbyopia that have beenapproved as safe and effective by the U.S. Food and Drug Administration.

Mydriasis is a disorder of the eye characterized by an unusually dilatedpupil, frequently caused by one or more of disease, trauma, or apharmacological agent. The pharmacological agent could be, for example,an agent administered to the eye to cause pupil dilation as part of aneye examination. Alternatively, the pharmacological agent could be anagent administered to the patient for other reasons, and may be a singleadministration of the agent to the patient or an agent administered onmultiple occasions. The negative effects of mydriasis can includesensitivity to light and inability to focus, particularly in brightenvironments. Existing treatments for mydriasis vary, based on the causeof the mydriasis, but are not effective for all patients and/or haveundesirable characteristics. One treatment for mydriasis described inthe literature is REV-EYES™ (dapiprazole hydrochloride ophthalmicsolution). A typical administration protocol for REV-EYES™ is toadminister two drops of the ophthalmic solution to the patient's eye andthen after five minutes administer an additional two drops of theophthalmic solution to the patient's eye. Some drawbacks of REV-EYES™are that it has been reported to cause a significant burning sensationupon administration, which is unpleasant for the patient, as well assignificant eye redness. The need exists for better treatments formydriasis.

The present invention addresses the aforementioned need for methods andcompositions for treating patients suffering from presbyopia, mydriasis,and other ocular disorders while minimizing undesirable side effects,and the invention provides other related advantages.

SUMMARY

The invention provides methods, compositions, and kits containing analpha-adrenergic antagonist, such as phentolamine, for use inmonotherapy or as part of a combination therapy to treat patientssuffering from presbyopia, mydriasis, and/or other ocular disorders. Thealpha-adrenergic antagonist, such as phentolamine, is administeredtopically to the eye of the patient, preferably in the form of a liquidaqueous ophthalmic formulation. Desirably the alpha-adrenergicantagonist is administered to the patient once daily, alone or incombination with an additional agent, in order to reduce pupil diameterof the patient, such as to have a pupil diameter of less than 2 mm, 1.8mm, or 1.6 mm, or to have a pupil diameter reduction of at least 1 mm, 2mm, 3 mm, or more. In certain embodiments, the alpha-adrenergicantagonist is administered to the patient once daily, alone or incombination with an additional agent, in order to reduce pupil diameterof the patient, such as to have a pupil diameter of less than 3.0, 2.8,2.6, 2.4, or 2.2 mm. Such reduction in pupil diameter due to thealpha-adrenergic antagonist provides therapeutic benefits to patientssuffering from presbyopia or mydriasis. The reduction in pupil diametermay be characterized according to the percent reduction in pupildiameter due to administering the alpha-adrenergic antagonist, such aswhere the reduction in pupil diameter is at least 5%, 10%, 15%, 20%,30%, or 40%. One benefit of therapeutic methods described herein is thatthe patient may experience an improvement in visual performance, forexample, an improvement in the patient's ability to see clearly and/orability to distinguish between an object and its background. Theimprovement in visual performance may include improvement in visualperformance at near distance and at far distance. Another benefit oftherapeutic methods described herein is that there are methods providinga once daily administration protocol, which is easier for patients thana dosing protocol that requires administration of therapeutic agent(s)multiple times per day. Yet another benefit of therapeutic methodsdescribed herein is that there are methods providing for rapid onset oftreatment, where, for example, therapeutic benefits can be observed asearly as within about 30 minutes after administering, for example, analpha-adrenergic antagonist such as phentolamine to an eye of thepatient. In certain embodiments, the therapeutic benefits can beobserved within 30 to 60 minutes after administering, for example, analpha-adrenergic antagonist such as phentolamine to an eye of thepatient. In certain embodiments, the therapeutic benefits can beobserved as early as within about 1 hour after administering, forexample, an alpha-adrenergic antagonist such as phentolamine to an eyeof the patient. Exemplary aspects and embodiments of the invention aredescribed below.

One aspect of the invention provides a method of treating presbyopia ina patient. The method comprises administering to an eye of a patient inneed thereof a dosage of an alpha-adrenergic antagonist in an amounteffective to thereby treat the presbyopia, wherein the dosage isadministered to the eye no more than once per day. The dosage may beadministered at or near the bedtime of the patient. One benefit of sucha dosing protocol is that it minimizes eye redness experienced by thepatient during the patient's waking hours, while achieving a reductionin pupil diameter that is desirable for treatment of presbyopia. Incertain embodiments, the dosage contains phentolamine mesylate.

Another aspect of the invention provides a method of treating presbyopiain a patient while minimizing eye redness during the patient's wakinghours. The method comprises administering to an eye of a patient in needthereof only at or near the bedtime of the patient a dosage of analpha-adrenergic antagonist in an amount effective to thereby treat thepresbyopia. One benefit of the dosing protocol is that it minimizes eyeredness experienced by the patient during the patient's waking hours,while achieving a reduction in pupil diameter that is desirable fortreatment of presbyopia. In certain embodiments, the dosage containsphentolamine mesylate. In certain embodiments, the method furthercomprises administering to said eye of the patient an additional agentthat facilitates reduction of the patient's pupil or improves visualperformance. In certain embodiments, the method further comprisesadministering to said eye of the patient an additional agent thatfacilitates reduction of the patient's pupil. In certain embodiments,the method further comprises administering to said eye of the patient anadditional agent that improves visual performance. In other embodiments,the alpha-adrenergic antagonist is the only agent administered thattreats presbyopia.

Another aspect of the invention provides a method of treating presbyopiain a patient according to a monotherapy treatment regimen. The methodcomprises administering to an eye of a patient in need thereof a dosageof a single therapeutic agent in an amount effective for treatment ofpresbyopia, wherein the single therapeutic agent is an alpha-adrenergicantagonist. The dosage may be administered to the eye of the patientaccording to a particular dosing protocol, such as administration to theeye of the patient once per day, which may be, for example, at or nearthe bed time of the patient. Such dosing protocol may entail, forexample, administering the dosage to the eye of the patient for at leastthree or seven consecutive days. In certain embodiments, the singletherapeutic agent is phentolamine mesylate.

Another aspect of the invention provides a method of treating mydriasisin a patient. The method comprises administering to an eye of a patientin need thereof a dosage of an alpha-adrenergic antagonist in an amounteffective to thereby treat the mydriasis. In certain embodiments, themydriasis is due to the patient having received one or more of anadrenergic or parasympatholyic agent. In certain embodiments, themydriasis is due to the patient having received one or more of an alphaagonist, a TAAR1 agonist, or NSAID. In certain embodiments, themydriasis is due to the patient having received one or more of atropine,cyclopentolate, homatropine, scopolamine, tropicamide, phenylephrine, ora pharmaceutically acceptable salt thereof. In certain embodiments, themydriasis is due to the patient having received one or more of atropine,cyclopentolate, homatropine, scopolamine, tropicamide, or apharmaceutically acceptable salt thereof. In certain embodiments, themydriasis is due to the patient having received one or more of atropine,cyclopentolate, homatropine, scopolamine, tropicamide, flubiprofen,suprofen, hydroxyamphetamine, phenylephrine, cyclopentolate, ketorolac,or a pharmaceutically acceptable salt thereof. In certain embodiments,the single therapeutic agent is phentolamine mesylate.

The invention also provides for reducing eye redness due toadministration of the alpha-adrenergic antagonist. In certainembodiments, the method further comprises administering an agent thatreduces eye redness. Exemplary agents that reduce eye redness includebrimonidine, tetrahydrozoline, oxymetazoline, naphthazoline, or apharmaceutically acceptable salt thereof, such as LUMIFY® (which is acommercially available ophthalmic solution containing brimonidinetartrate (0.025% w/w)).

Another aspect of the invention provides a pharmaceutical compositioncomprising an alpha-adrenergic antagonist and a second therapeutic agentselected from the group consisting of a muscarinic acetylcholinereceptor agonist, an alpha-2 adrenergic agonist, a prostaglandin, and alipoic acid choline ester. Preferably, the pharmaceutical composition isformulated for ophthalmic administration.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts exemplary eye redness as measured according to (1) theCCLRU Redness Grading Scale, and (2) the NYX-001 Redness Grading Scale.

FIG. 2 is a graph showing observed change in pupil diameter observed inthe clinical study described in Example 5.

FIG. 3 is a graph showing observed eye redness observed in the clinicalstudy described in Example 5.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods, compositions, and kits containing analpha-adrenergic antagonist, such as phentolamine, for use inmonotherapy or as part of a combination therapy to treat patientssuffering from presbyopia, mydriasis, and/or other ocular disorders. Thealpha-adrenergic antagonist, such as phentolamine, is administeredtopically to the eye of the patient, preferably in the form of a liquidaqueous ophthalmic formulation. Desirably the alpha-adrenergicantagonist is administered to the patient once daily, alone or incombination with an additional agent, in order to reduce pupil diameterof the patient, such as to have a pupil diameter of less than 2 mm, 1.8mm, or 1.6 mm, or to have a pupil diameter reduction of at least 1 mm, 2mm, 3 mm, or more. In certain embodiments, the alpha-adrenergicantagonist is administered to the patient once daily, alone or incombination with an additional agent, in order to reduce pupil diameterof the patient, such as to have a pupil diameter of less than 3.0, 2.8,2.6, 2.4, or 2.2 mm. The reduction in pupil diameter may becharacterized according to the percent reduction in pupil diameter dueto administering the alpha-adrenergic antagonist, such as where thereduction in pupil diameter is at least 5%, 10%, 15%, 20%, 30%, or 40%.Such reduction in pupil diameter due to the alpha-adrenergic antagonistprovides therapeutic benefits to patients suffering from presbyopia ormydriasis. One benefit of therapeutic methods described herein is thatthe patient may experience an improvement in visual performance, forexample, an improvement in the patient's ability to see clearly and/orability to distinguish between an object and its background. Theimprovement in visual performance may include improvement in visualperformance at near distance and at far distance. Another benefit oftherapeutic methods described herein is that there are methods providinga once daily administration protocol, which is easier for patients thana dosing protocol that requires administration of therapeutic agent(s)multiple times per day. Yet another benefit of therapeutic methodsdescribed herein is that there are methods providing for rapid onset oftreatment, where, for example, therapeutic benefits can be observed asearly as within about 30 minutes after administering, for example, analpha-adrenergic antagonist such as phentolamine to an eye of thepatient. In certain embodiments, the therapeutic benefits can beobserved within 30 to 60 minutes after administering, for example, analpha-adrenergic antagonist such as phentolamine to an eye of thepatient. In certain embodiments, the therapeutic benefits can beobserved as early as within about 1 hour after administering, forexample, an alpha-adrenergic antagonist such as phentolamine to an eyeof the patient. Exemplary aspects and embodiments of the invention aredescribed below. Various aspects of the invention are set forth below insections; however, aspects of the invention described in one particularsection are not to be limited to any particular section.

Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a,” “an” and “the” as used herein mean “one or more” andinclude the plural unless the context is inappropriate.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyincludes humans.

As used herein, the term “effective amount” refers to the amount of acompound sufficient to effect beneficial or desired results. Unlessspecified otherwise, an effective amount can be administered in one ormore administrations, applications or dosages and is not intended to belimited to a particular formulation or administration route. As usedherein, the term “treating” includes any effect, e.g., lessening,reducing, modulating, ameliorating or eliminating, that results in theimprovement of the condition, disease, disorder, and the like, orameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for therapeutic use in vivo or exvivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin inRemington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention. As is known to thoseof skill in the art, “salts” of the compounds of the present inventionmay be derived from inorganic or organic acids and bases. Examples ofacids include, but are not limited to, hydrochloric, hydrobromic,sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic,lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic,citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic,naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids,such as oxalic, while not in themselves pharmaceutically acceptable, maybe employed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₃, wherein W is C₁₋₄ alkyl, and thelike.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate,oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate,pivalate, propionate, succinate, sulfate, tartrate, thiocyanate,tosylate, undecanoate, and the like. Other examples of salts includeanions of the compounds of the present invention compounded with asuitable cation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄ alkylgroup), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The term “alkanoate” is art-recognized and refers to alkyl-C(O)O⁻.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and alternatively about 5, 6 or 7 carbons in the ringstructure.

As used herein, the term “EV06” refers to a compound having thefollowing chemical structure:

an optical isomer, or a mixture thereof, where Z is an anion. Anion Z⁻can be any pharmaceutically acceptable anion. Non-limiting examples ofanions include chloride, bromide, iodide, sulfate, methanesulfonate,nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate,tartrate (e.g., (+)-tartrate, (−)-tartrate, or a mixture thereof),succinate, benzoate, and anions of an amino acid such as glutamic acid.In some embodiments, the anion is chloride. In some embodiments, theanion is tartrate.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

I. Therapeutic Methods

The invention provides methods for treating patients suffering frompresbyopia, mydriasis, and/or other ocular disorders by administering tothe eye of the patient an alpha-adrenergic antagonist, such asphentolamine. The alpha-adrenergic antagonist is administered topicallyto the eye of the patient, preferably in the form of a liquid aqueousophthalmic formulation. Various aspects and embodiments of thetherapeutic methods are described in the sections below. The sectionsare arranged for convenience and information in one section is not to belimited to that section, but may be applied to methods in othersections.

A. First Method

One aspect of the invention provides a method of treating presbyopia ina patient, comprising administering to an eye of a patient in needthereof a dosage of an alpha-adrenergic antagonist in an amounteffective to thereby treat the presbyopia, wherein the dosage isadministered to the eye no more than once per day.

The method may be further characterized by additional features, such asthe dosing regimen and the identity of the dosage, as described in moredetail below. The invention embraces all permutations and combinationsof these features. For example, in certain embodiments, the dosage isadministered at or near the bedtime of the patient. In certainembodiments, the dosage is administered within 1 hour of the patient'sbedtime.

In certain embodiments, the dosage comprises a pharmaceuticallyacceptable salt of phentolamine. In certain embodiments, the dosagecomprises phentolamine mesylate.

B. Second Method

Another aspect of the invention provides a method of treating presbyopiain a patient while minimizing eye redness during the patient's wakinghours, comprising administering to an eye of a patient in need thereofonly at or near the bedtime of the patient a dosage of analpha-adrenergic antagonist in an amount effective to thereby treat thepresbyopia.

The method may be further characterized by additional features, such asthe dosing regimen and the administration, identity, and amount of anadditional agent, as described in more detail below. The inventionembraces all permutations and combinations of these features. Forexample, in certain embodiments, the dosage is administered to the eyeno more than once per day. In certain embodiments, the dosage comprisesa pharmaceutically acceptable salt of phentolamine. In certainembodiments, the dosage comprises phentolamine mesylate.

C. Third Method

Another aspect of the invention provides a method of treating presbyopiain a patient, comprising administering to an eye of a patient in needthereof a dosage of an alpha-adrenergic antagonist in an amounteffective to thereby treat the presbyopia.

The method may be further characterized by additional features, such asthe dosing regimen and the administration, identity, and amount of anadditional agent, as described in more detail below. The inventionembraces all permutations and combinations of these features.

In certain embodiments, the dosage is administered to the patient daily.In certain embodiments, the dosage is administered to the patient twiceper day. In certain embodiments, the dosage comprises a pharmaceuticallyacceptable salt of phentolamine. In certain embodiments, the dosagecomprises phentolamine mesylate.

In certain embodiments, the dosage of alpha-adrenergic antagonist is 1%w/w phentolamine mesylate solution. In certain embodiments, the dosageof alpha-adrenergic antagonist is 1.5% w/w phentolamine mesylatesolution. In certain embodiments, the dosage of alpha-adrenergicantagonist is 2% w/w phentolamine mesylate solution.

In certain embodiments, the dosage is administered as a single eye drop.In certain embodiments, the dosage is administered as two eye drops.

In certain embodiments, the dosage is administered to the patient as afixed dose combination with an additional therapeutic agent. In certainembodiments, the additional therapeutic agent is pilocarpine.

D. Additional Features of the First, Second, and Third TherapeuticMethods

The First, Second, and Third Therapeutic Methods may be furthercharacterized according additional features. One feature is whether anadditional agent is administered (e.g., an agent that facilitatesreduction of the patient's pupil or improves visual performance).Another feature is whether the dosage of alpha-adrenergic antagonist isadministered sequentially or concurrently with an additional agent.

In certain embodiments, the method further comprises administering tosaid eye of the patient an additional agent that facilitates reductionof the patient's pupil or improvement in visual performance. In certainembodiments, the method further comprises administering to said eye ofthe patient an additional agent that facilitates reduction of thepatient's pupil. This desirably results in further reduction in thepatient's pupil diameter beyond that achieved when administering justthe alpha-adrenergic antagonist. In certain embodiments, the methodfurther comprises administering to said eye of the patient an additionalagent that facilitates improvement in visual performance.

In certain embodiments, the additional agent is administered to said eyeof the patient concurrently with the dosage of alpha-adrenergicantagonist. In certain embodiments, the additional agent is administeredto said eye of the patient sequentially either before or afteradministering to said eye of the patient the dosage of alpha-adrenergicantagonist.

The method may be further characterized according to the amount ofadditional agent administered to an eye of the patient. For example, incertain embodiments, the additional agent is administered to the eye ofthe patient in an amount ranging from about 0.0001 mg to about 0.001 mg.In certain embodiments, the additional agent is administered to the eyeof the patient in an amount ranging from about 0.001 mg to about 0.01mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.01 mg to about 0.1mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.1 mg to about 0.5mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.5 mg to about 1.0mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 1.0 mg to about 1.5mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 1.5 mg to about 2.0mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 2.0 mg to about 2.5mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 2.5 mg to about 3.0mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 2.5 mg to about 3.0mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.001 mg to about 0.1mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.1 mg to about 1.0mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 1.0 mg to about 2.0mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.1 mg to about 0.125mg. In certain embodiments, the additional agent is administered to theeye of the patient in an amount ranging from about 0.125 mg to about0.25 mg. In certain embodiments, the additional agent is administered tothe eye of the patient in an amount ranging from about 0.25 mg to about0.50 mg. In certain embodiments, the additional agent is administered tothe eye of the patient in an amount ranging from about 0.50 mg to about0.75 mg. In certain embodiments, the additional agent is administered tothe eye of the patient in an amount ranging from about 0.75 mg to about1.0 mg. In certain embodiments, the additional agent is administered tothe eye of the patient in an amount ranging from about 1.25 mg to about1.5 mg.

The method may be further characterized according to the identity of theadditional agent. In certain embodiments, the additional agent improvesvisual performance. In certain embodiments, the additional agentfacilitates reduction of the patient's pupil. In certain embodiments,the additional agent is selected from the group consisting of amuscarinic acetylcholine receptor agonist, an alpha-2 adrenergicagonist, a prostaglandin, and a lipoic acid choline ester.

In certain embodiments, the additional agent is a muscarinicacetylcholine receptor agonist.

In certain embodiments, the additional agent is pilocarpine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is pilocarpine hydrochloride. In certain embodiments,the additional agent is administered to the eye of the patient in anamount ranging from about 0.1 mg to about 1.0 mg. In certainembodiments, the additional agent is administered to the eye of thepatient in an amount ranging from about 0.1 mg to about 0.3 mg. Incertain embodiments, the additional agent is administered to the eye ofthe patient in an amount of about 0.2 mg. In certain other embodiments,the additional agent is administered to the eye of the patient in anamount ranging from about 0.3 mg to about 0.6 mg.

In certain embodiments, the additional agent is pilocarpine or apharmaceutically acceptable salt thereof, which is administered to thepatient in the form of an ophthalmic solution. In certain embodiments,the ophthalmic solution contains pilocarpine or pharmaceuticallyacceptable salt thereof in the amount of from about 0.1% w/w to about 3%w/w. In certain embodiments, the ophthalmic solution containspilocarpine or pharmaceutically acceptable salt thereof in the amount offrom about 0.2% w/w to about 0.4% w/w. In certain embodiments, theophthalmic solution contains pilocarpine or pharmaceutically acceptablesalt thereof in the amount of from about 1% w/w to about 2% w/w. Incertain embodiments, the one drop of the ophthalmic solution containingpilocarpine or pharmaceutically acceptable salt is administered to thepatient's eye.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises pilocarpine in an amount ranging from about 0.001% to about0.1% w/w, about 0.001% to about 2% w/w, about 0.01% to about 2% w/w, orabout 0.01% to about 4% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises pilocarpine in an amount of about 0.01%,0.25%, 0.5%, 1%, 2%, or 4% w/w.

In certain embodiments, the additional agent is carbachol or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is carbachol. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.5 mg to about 2.5 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.5 mg to about 1.0 mg. In certain other embodiments,the additional agent is administered to the eye of the patient in anamount ranging from about 1.0 mg to about 1.5 mg. In certainembodiments, the additional agent is administered to the eye of thepatient in an amount of about 1.2 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises carbochol in an amount ranging from about 0.001% to about 0.1%w/w, about 0.001% to about 3% w/w, about 0.1% to about 1.5% w/w, orabout 0.1% to about 2% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises carbochol in an amount of about 0.1%,0.25%, 0.5%, 0.75, 1.5%, 2%, 2.25%, or 3% w/w.

In certain embodiments, the additional agent is bethanechol or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is a bethanechol salt. In certain embodiments, theadditional agent is bethanechol chloride. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.1 mg to about 3 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.1 mg to about 1 mg. In certain other embodiments,the additional agent is administered to the eye of the patient in anamount ranging from about 1 mg to about 2 mg. In certain embodiments,the additional agent is administered to the eye of the patient in anamount of about 1.2 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises bethanechol chloride in an amount ranging from about 0.001% toabout 0.1% w/w, about 0.001% to about 0.01% w/w, or about 0.01% to about0.1% w/w. In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises bethanechol chloride in an amount of about 0.001%, 0.01%, or0.1% w/w.

In certain embodiments, the additional agent is aceclidine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is aceclidine hydrochloride. In certain embodiments,the additional agent is administered to the eye of the patient in anamount ranging from about 0.01 mg to about 4 mg. In certain embodiments,the additional agent is administered to the eye of the patient in anamount ranging from about 0.01 mg to about 0.1 mg. In certainembodiments, the additional agent is administered to the eye of thepatient in an amount of about 0.01 mg. In certain other embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.1 mg to about 1.5 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises aceclidine hydrochloride in an amount ranging from about0.001% to about 0.1% w/w, about 0.001% to about 1.5% w/w, about 0.001%to about 3% w/w, about 1.35% to about 1.65% w/w, or about 0.01% to about2% w/w. In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises aceclidine hydrochloride in an amount of about 0.01%, 0.1%,0.25%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% w/w.

In certain embodiments, the additional agent is oxotremorine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is oxotremorine. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.1 mg to about 1.0 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.1 mg to about 0.3 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.2 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.3 mg to about 0.6 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises oxotremorine in an amount ranging from about 0.001% to about0.1% w/w, about 0.001% to about 2% w/w, about 0.01% to about 2% w/w, orabout 0.01% to about 4% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises oxotremorine in an amount of about 0.01%,0.25%, 0.5%, 1%, 2%, or 4% w/w.

In certain embodiments, the additional agent is methacholine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is methacholine. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.1 mg to about 1.0 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.1 mg to about 0.3 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.2 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.3 mg to about 0.6 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises methacholine in an amount ranging from about 0.001% to about0.1% w/w, about 0.001% to about 2% w/w, about 0.01% to about 2% w/w, orabout 0.01% to about 4% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises methacholine in an amount of about 0.01%,0.25%, 0.5%, 1%, 2%, or 4% w/w.

In certain embodiments, the additional agent is muscarine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is muscarine. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.1 mg to about 1.0 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.1 mg to about 0.3 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.2 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.3 mg to about 0.6 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises muscarine in an amount ranging from about 0.001% to about 0.1%w/w, about 0.001% to about 2% w/w, about 0.01% to about 2% w/w, or about0.01% to about 4% w/w. In certain embodiments, one drop of an ocularformulation is administered to an eye of the patient, wherein the ocularformulation comprises muscarine in an amount of about 0.01%, 0.25%,0.5%, 1%, 2%, or 4% w/w.

In certain embodiments, the additional agent is an alpha-2 adrenergicagonist. In certain embodiments, the additional agent is brimonidine ora pharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is brimonidine tartrate. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 4 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.1 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.1 mg to about 1 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises brimonidine tartrate in an amount ranging from about 0.01% toabout 4% w/w, about 0.02% to about 4% w/w, about 0.02% to about 0.2%w/w, about 0.2% to about 3% w/w, or about 0.01% to about 2% w/w. Incertain embodiments, one drop of an ocular formulation is administeredto an eye of the patient, wherein the ocular formulation comprisesbrimonidine tartrate in an amount of about 0.01%, 0.02%, 0.1%, 0.2%,0.5%, 1%, 1.5%, 2%, 3%, or 4% w/w.

In certain embodiments, the additional agent is carbamoylcholine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 4 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.1 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.1 mg to about 1 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises carbamoylcholine or a pharmaceutically acceptable salt thereofin an amount ranging from about 0.01% to about 4% w/w, about 0.02% toabout 4% w/w, about 0.02% to about 0.2% w/w, about 0.2% to about 3% w/w,or about 0.01% to about 2% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises carbamoylcholine or a pharmaceuticallyacceptable salt thereof in an amount of about 0.01%, 0.02%, 0.1%, 0.2%,0.5%, 1%, 1.5%, 2%, 3%, or 4% w/w.

In certain embodiments, the additional agent is physostigmine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 4 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.1 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.1 mg to about 1 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises physostigmine or a pharmaceutically acceptable salt thereof inan amount ranging from about 0.01% to about 4% w/w, about 0.02% to about4% w/w, about 0.02% to about 0.2% w/w, about 0.2% to about 3% w/w, orabout 0.01% to about 2% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises physostigmine or a pharmaceuticallyacceptable salt thereof in an amount of about 0.01%, 0.02%, 0.1%, 0.2%,0.5%, 1%, 1.5%, 2%, 3%, or 4% w/w.

In certain embodiments, the additional agent is echothiophate or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 4 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.1 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.1 mg to about 1 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises echothiophate or a pharmaceutically acceptable salt thereof inan amount ranging from about 0.01% to about 4% w/w, about 0.02% to about4% w/w, about 0.02% to about 0.2% w/w, about 0.2% to about 3% w/w, orabout 0.01% to about 2% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises echothiophate or a pharmaceuticallyacceptable salt thereof in an amount of about 0.01%, 0.02%, 0.1%, 0.2%,0.5%, 1%, 1.5%, 2%, 3%, or 4% w/w.

In certain embodiments, the additional agent is acetylcholine or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 4 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.01 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountof about 0.1 mg. In certain other embodiments, the additional agent isadministered to the eye of the patient in an amount ranging from about0.1 mg to about 1 mg.

In certain embodiments, one drop of an ocular formulation isadministered to an eye of the patient, wherein the ocular formulationcomprises acetylcholine or a pharmaceutically acceptable salt thereof inan amount ranging from about 0.01% to about 4% w/w, about 0.02% to about4% w/w, about 0.02% to about 0.2% w/w, about 0.2% to about 3% w/w, orabout 0.01% to about 2% w/w. In certain embodiments, one drop of anocular formulation is administered to an eye of the patient, wherein theocular formulation comprises acetylcholine or a pharmaceuticallyacceptable salt thereof in an amount of about 0.01%, 0.02%, 0.1%, 0.2%,0.5%, 1%, 1.5%, 2%, 3%, or 4% w/w.

In certain embodiments, the additional agent is a prostaglandin. Incertain embodiments, the additional agent is dinoprostone or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is dinoprostone. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.1 mg to about 4 mg. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.1 mg to about 1 mg. In certain other embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 1 mg to about 3 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.001 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.0025 mg to about 0.01 mg. In certain embodiments,the additional agent is administered to the eye of the patient in anamount of about 0.0025 mg. In certain embodiments, one drop of an ocularformulation is administered to an eye of the patient, wherein the ocularformulation comprises dinoprostone in an amount of about 0.002%, 0.003%,0.004%, 0.005%, 0.006%, 0.007%, or 0.01% w/w.

In certain embodiments, the additional agent is latanaprost or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is latanaprost. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.001 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.0025 mg to about 0.01 mg. In certain embodiments,the additional agent is administered to the eye of the patient in anamount of about 0.0025 mg. In certain embodiments, one drop of an ocularformulation is administered to an eye of the patient, wherein the ocularformulation comprises latanaprost in an amount of about 0.002%, 0.003%,0.004%, 0.005%, 0.006%, 0.007%, or 0.01% w/w. In certain embodiments,the additional agent is latanaprost, which is administered to the eye ofthe patient in an amount ranging from about 0.5 to about 1.0 micrograms,about 1.0 to about 1.5 micrograms, about 1.5 to about 2.0 micrograms oflatanaoprost, or about 2.0 to about 5.0 micrograms of latanaoprost.

In certain embodiments, the additional agent is bimatoprost or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is bimatoprost. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.001 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.001 mg to about 0.003 mg. In certain embodiments,the additional agent is administered to the eye of the patient in anamount of about 0.002 mg. In certain embodiments, one drop of an ocularformulation is administered to an eye of the patient, wherein the ocularformulation comprises bimatoprost in an amount of about 0.001%, 0.005%,0.008%, 0.009, 0.01%, 0.02%, 0.03%, 0.04%, or 0.05% w/w.

In certain embodiments, the additional agent is travoprost or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is travoprost. In certain embodiments, the additionalagent is administered to the eye of the patient in an amount rangingfrom about 0.001 mg to about 0.1 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.001 mg to about 0.01 mg. In certain embodiments,the additional agent is administered to the eye of the patient in anamount of about 0.005 mg. In certain embodiments, one drop of an ocularformulation is administered to an eye of the patient, wherein the ocularformulation comprises travoprost in an amount of about 0.002%, 0.003%,0.004%, 0.005%, 0.006%, 0.007%, or 0.01% w/w.

In certain embodiments, the additional agent is EV06 or apharmaceutically acceptable salt thereof. In certain embodiments, theadditional agent is EV06 chloride. In certain embodiments, theadditional agent is EV06 tartrate. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.25 mg to about 1.2 mg. In certain embodiments, theadditional agent is administered to the eye of the patient in an amountranging from about 0.25 mg to about 0.5 mg. In certain otherembodiments, the additional agent is administered to the eye of thepatient in an amount ranging from about 0.5 mg to about 0.75 mg. Incertain embodiments, the additional agent is administered to the eye ofthe patient in an amount of about 0.6 mg.

In certain embodiments, the additional agent is a cholinesteraseinhibitor.

In certain embodiments, yet another therapeutic agent is administered tothe eye of the patient. In such embodiments, the method furthercomprises administering to the eye of the patient an alpha adrenergicagonist, such as brimonidine or a pharmaceutically acceptable saltthereof.

E. Fourth Method

Another aspect of the invention provides a method of treating presbyopiain a patient according to a monotherapy treatment regimen, comprisingadministering to an eye of a patient in need thereof a dosage of asingle therapeutic agent in an amount effective for treatment ofpresbyopia, wherein the single therapeutic agent is an alpha-adrenergicantagonist.

The method may be further characterized by additional features, such asthe dosing regimen and the identity of the dosage, as described in moredetail below. The invention embraces all permutations and combinationsof these features.

Accordingly, in certain embodiments, the dosage is administered at ornear the bedtime of the patient. In certain embodiments, the dosage isadministered within 1 hour of the patient's bedtime. In certainembodiments, the dosage comprises a pharmaceutically acceptable salt ofphentolamine. In certain embodiments, the dosage comprises phentolaminemesylate.

In certain embodiments, the dosage of a single therapeutic agent is 1%w/w phentolamine mesylate solution. In certain embodiments, the dosageof a single therapeutic agent is 1.5% w/w phentolamine mesylatesolution. In certain embodiments, the dosage of a single therapeuticagent is 2% w/w phentolamine mesylate solution.

In certain embodiments, the dosage is administered as a single eye drop.In certain embodiments, the dosage is administered as two eye drops.

F. Fifth Method

Another aspect of the invention provides a method of treating mydriasisin a patient, comprising administering to an eye of a patient in needthereof a dosage of an alpha-adrenergic antagonist in an amounteffective to thereby treat the mydriasis.

The method may be further characterized by additional features, such asthe cause of the mydriasis and the amount of reduction in pupil diameterthe patient experiences. The invention embraces all permutations andcombinations of these features.

Accordingly, in certain embodiments, the mydriasis is due to the patienthaving received an agent that causes pupil dilation. In certainembodiments, the mydriasis is due to the patient having received one ormore of an adrenergic or parasympatholyic agent. In certain embodiments,the mydriasis is due to the patient having received one or more of analpha agonist, a TAAR1 agonist, or NSAID. In certain embodiments, themydriasis is due to the patient having received one or more of atropine,cyclopentolate, homatropine, scopolamine, tropicamide, flubiprofen,suprofen, hydroxyamphetamine, phenylephrine, cyclopentolate, ketorolac,or a pharmaceutically acceptable salt thereof. In certain embodiments,the mydriasis is due to the patient having received one or more ofatropine, cyclopentolate, homatropine, scopolamine, tropicamide,phenylephrine, or a pharmaceutically acceptable salt thereof. In certainembodiments, the mydriasis is due to the patient having received one ormore of atropine, cyclopentolate, homatropine, scopolamine, tropicamide,or a pharmaceutically acceptable salt thereof. In certain embodiments,the mydriasis is due to the patient having received atropine,homatropine, scopolamine, or a pharmaceutically acceptable salt thereof.In certain embodiments, the mydriasis is due to the patient havingreceived cyclopentolate or a pharmaceutically acceptable salt thereof.In certain embodiments, the mydriasis is due to the patient havingreceived tropicamide or a pharmaceutically acceptable salt thereof. Incertain embodiments, the mydriasis is due to the patient having receivedphenylephrine or a pharmaceutically acceptable salt thereof.

In certain embodiments, the mydriasis is due to the patient havingreceived flubiprofen or a pharmaceutically acceptable salt thereof. Incertain embodiments, the mydriasis is due to the patient having receivedflubiprofen sodium. In certain embodiments, the mydriasis is due to thepatient having received suprofen or a pharmaceutically acceptable saltthereof. In certain embodiments, the mydriasis is due to the patienthaving received hydroxyamphetamine or a pharmaceutically acceptable saltthereof. In certain embodiments, the mydriasis is due to the patienthaving received tropicamide or a pharmaceutically acceptable saltthereof. In certain embodiments, the mydriasis is due to the patienthaving received cyclopentolate or a pharmaceutically acceptable saltthereof. In certain embodiments, the mydriasis is due to the patienthaving received ketorolac or a pharmaceutically acceptable salt thereof.In certain embodiments, the mydriasis is due to the patient havingreceived hydroxyamphetamine hydrobromide and tropicamide, which ismarketed as PAREMYD®. In certain embodiments, the mydriasis is due tothe patient having received cyclopentolate hydrochloride andphenylephrine hydrochloride, which is marketed as CYCLOMYDRIL®. Incertain embodiments, the mydriasis is due to the patient having receivedscopolamine and phenylephrine. In certain embodiments, the mydriasis isdue to the patient having received ketorolac and phenylephrine, which ismarketed as OMIDRIA®.

The method may be further characterized according to the dosing regimen.For example, in certain embodiments, the dosage is administered to theeye no more than once per day. In certain embodiments, the dosage isadministered to the eye no more than once every two days. In certainembodiments, the dosage is administered to the eye of the patient afterthe patient has completed an eye examination in which a pupil dilatingagent was administered to the patient's eye.

The method may be further characterized according to the amount ofreduction in pupil diameter. For example, in certain embodiments, thepatient experiences at least a 1 mm reduction in pupil diameter whenmeasured under mesopic conditions relative to the diameter of thepatient's pupil under the same mesopic conditions but not havingreceived said dosage. In certain embodiments, the patient experiences atleast a 2 mm reduction in pupil diameter when measured under mesopicconditions relative to the diameter of the patient's pupil under thesame mesopic conditions but not having received said dosage. In certainembodiments, the patient experiences at least a 3 mm reduction in pupildiameter when measured under mesopic conditions relative to the diameterof the patient's pupil under the same mesopic conditions but not havingreceived said dosage. In certain embodiments, the patient experiences atleast a 4 mm, 5 mm, or greater reduction in pupil diameter when measuredunder mesopic conditions relative to the diameter of the patient's pupilunder the same mesopic conditions but not having received said dosage.In certain other embodiments, the patient experiences a reduction inpupil diameter ranging from about 0.5 mm to about 5 mm when measuredunder mesopic conditions relative to the diameter of the patient's pupilunder the same mesopic conditions but not having received said dosage.

In certain embodiments, the patient experiences at least a 1 mmreduction in pupil diameter when measured under photopic conditionsrelative to the diameter of the patient's pupil under the same photopicconditions but not having received said dosage. In certain embodiments,the patient experiences at least a 2 mm reduction in pupil diameter whenmeasured under photopic conditions relative to the diameter of thepatient's pupil under the same photopic conditions but not havingreceived said dosage. In certain embodiments, the patient experiences atleast a 3 mm reduction in pupil diameter when measured under photopicconditions relative to the diameter of the patient's pupil under thesame photopic conditions but not having received said dosage. In certainembodiments, the patient experiences at least a 4 mm, 5 mm, or greaterreduction in pupil diameter when measured under photopic conditionsrelative to the diameter of the patient's pupil under the same photopicconditions but not having received said dosage. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.5 mm to about 5 mm when measured under photopicconditions relative to the diameter of the patient's pupil under thesame photopic conditions but not having received said dosage.

In certain embodiments, the patient experiences at least a 1 mmreduction in pupil diameter relative to the diameter of the patient'spupil measured under the same conditions (e.g., mesopic or photopic) butnot having received said dosage. In certain embodiments, the patientexperiences at least a 2 mm reduction in pupil diameter relative to thediameter of the patient's pupil measured under the same conditions(e.g., mesopic or photopic) but not having received said dosage. Incertain embodiments, the patient experiences at least a 3 mm reductionin pupil diameter relative to the diameter of the patient's pupilmeasured under the same conditions (e.g., mesopic or photopic) but nothaving received said dosage. In certain embodiments, the patientexperiences at least a 4 mm, 5 mm, or greater reduction in pupildiameter relative to the diameter of the patient's pupil measured underthe same conditions (e.g., mesopic or photopic) but not having receivedsaid dosage. In certain embodiments, the patient experiences at least a4 mm, 5 mm, or greater reduction in pupil diameter relative to thediameter of the patient's pupil measured under the same conditions(e.g., mesopic or photopic) but not having received said dosage. Incertain other embodiments, the patient experiences a reduction in pupildiameter ranging from about 0.5 mm to about 5 mm relative to thediameter of the patient's pupil under the same conditions (e.g., mesopicor photopic) but not having received said dosage.

G. Sixth Method

Another aspect of the invention provides a method of preventingprogressive myopia in a patient, comprising administering to an eye of apatient in need thereof a dosage of an alpha-adrenergic antagonist in anamount effective to thereby prevent progressive myopia.

The method may be further characterized by additional features. Forexample, in certain embodiments, the patient is an adult human. Incertain other embodiments, the patient is a pediatric human. In certainembodiments, the method further comprises administering to the eye ofthe patient one or more additional agents described herein. Theinvention embraces all permutations and combinations of these features.

H. Additional Features of the First, Second, Third and FourthTherapeutic Methods

Additional features that may characterize the First, Second, Third, andFourth therapeutic methods described herein (e.g., the methods describedin Parts A-D above) are provided below and include, for example, thedegree of eye redness, the dosing regimen of the alpha-adrenergicantagonist, the duration of the therapeutic effect against presbyopia,and the pupil diameter in the eye that received the dosage. A morethorough description of such features is provided below. The inventionembraces all permutations and combinations of these features.

Degree of Eye Redness

The methods may be further characterized according to the degree of eyeredness the patient experiences. The degree of eye redness can beevaluated and characterized using procedures described in theliterature, such as the Cornea and Contact Lens Research Unit (CCLRU)Redness Grading Scale developed by the School of Optometry, Universityof New South Wales. See, for example, Terry et al. in Optom. Vis. Sci.(1993) vol. 70, pages 234-243; and Pult et al. in Ophthal. Physiol. Opt.(2008) vol. 28, pages 13-20. The CCLRU Redness Grading Scale evaluateseye redness on a four-point scale: (0) no eye redness, (1) very slighteye redness, (2) slight eye redness, (3) moderate eye redness, and (4)severe eye redness. See FIG. 1 for an illustration of the eye rednessscale.

In certain embodiments, the patient experiences an increase in eyeredness of no more than two grades measured using the CCLRU RednessGrading Scale during the patient's waking hours compared to thepatient's level of eye redness without receiving said dosage ofalpha-adrenergic antagonist. In certain embodiments, the patientexperiences an increase in eye redness of no more than one grademeasured using the CCLRU Redness Grading Scale during the patient'swaking hours compared to the patient's level of eye redness withoutreceiving said dosage of alpha-adrenergic antagonist. In certainembodiments, any increase in eye redness experienced by the patient isless than one grade measured using the CCLRU Redness Grading Scaleduring the patient's waking hours compared to the patient's level of eyeredness without receiving said dosage of alpha-adrenergic antagonist.

Dosing Regimen of the Alpha-Adrenergic Antagonist

The methods may be further characterized according to the dosing regimenof the alpha-adrenergic antagonist. For example, in certain embodiments,the dosage of alpha-adrenergic antagonist is administered on a dailybasis.

In certain embodiments, the dosage of alpha-adrenergic antagonist isadministered for at least three consecutive days. In certainembodiments, the dosage of alpha-adrenergic antagonist is administeredfor at least seven consecutive days. In certain embodiments, the dosageof alpha-adrenergic antagonist is administered for at least fourteenconsecutive days.

In certain embodiments, the dosage is administered one per day. Incertain embodiments, the dosage is administered multiple times per day,such as two or three times per day.

In certain embodiments, the dosage is administered as a single eye drop.In certain embodiments, the dosage is administered as two eye drops.

Duration of Therapeutic Effect Against Presbyopia

The methods may be further characterized according to the duration ofthe therapeutic effect against presbyopia. For example, in certainembodiments, the method provides a therapeutic effect against presbyopiafor a duration of at least 6 hours. In certain embodiments, the methodprovides a therapeutic effect against presbyopia for a duration of atleast 12 hours. In certain embodiments, the method provides atherapeutic effect against presbyopia for a duration of at least 16hours. In certain embodiments, the method provides a therapeutic effectagainst presbyopia for a duration of at least 18 hours. In certainembodiments, the method provides a therapeutic effect against presbyopiafor a duration of at least 20 hours. In certain embodiments, the methodprovides a therapeutic effect against presbyopia for a duration of atleast 24 hours. In certain embodiments, the method provides atherapeutic effect against presbyopia for a duration of at least 36hours. In certain embodiments, the method provides a therapeutic effectagainst presbyopia for a duration of at least 48 hours.

Improvement in Patient's Vision

The methods may be further characterized according to the improvement inthe patient's vision. For example, in certain embodiments, the methodprovides an improvement in visual acuity characterized by at least aone-line improvement in the patient's vision measured using a visionchart. In certain embodiments, the method results in an improvement invisual acuity characterized by at least a two-line improvement in thepatient's vision measured using a vision chart. In certain embodiments,the method results in an improvement in visual acuity characterized byat least a three-line improvement in the patient's vision measured usinga vision chart. In certain embodiments, the method results in animprovement in visual acuity characterized by an improvement in thepatient's vision of four or more lines measured using a vision chart. Incertain embodiments, the vision chart is a Snellen chart. In certainother embodiments, the vision chart is a Jaeger chart. In certain otherembodiments, the vision chart is a Rosenbaum chart or an ETDRS chart. Incertain embodiments, the improvement in visual acuity is measured at anear distance (e.g., about 1, 2, or 3 feet). In certain embodiments, theimprovement in visual acuity is measured at a far distance (e.g., about20, 25, or 30 feet). In certain embodiments, the improvement in visualacuity is an improvement in near-vision visual acuity. In certainembodiments, the improvement in visual acuity is an improvement indistance visual acuity. In certain embodiments, the improvement invisual acuity is (i) an improvement in near-vision visual acuity and(ii) an improvement in distance visual acuity.

The method may be further characterized according to the duration of theimprovement in the patient's vision. In certain embodiments, the patientexperiences said improvement for a duration of at least 6 hours. Incertain embodiments, the patient experiences said improvement for aduration of at least 12 hours. In certain embodiments, the patientexperiences said improvement for a duration of at least 18 hours. Incertain embodiments, the patient experiences said improvement for aduration of at least 20 hours. In certain embodiments, the patientexperiences said improvement for a duration of at least 24 hours. Incertain embodiments, the patient experiences said improvement for aduration of at least 30 hours. In certain embodiments, the patientexperiences said improvement for a duration of at least 48 hours.

Pupil Diameter in the Eye that Received the Dosage

The methods may be further characterized according to the pupil diameterin the eye that received the dosage and the duration that said pupildiameter is maintained. For example, in certain embodiments, as a resultof the administering, the patient experiences the effect of having apupil diameter of less than 3.0 in the eye that received said dosagewhen measured under photopic conditions. In certain embodiments, as aresult of the administering, the patient experiences the effect ofhaving a pupil diameter of less than 2.8 in the eye that received saiddosage when measured under photopic conditions. In certain embodiments,as a result of the administering, the patient experiences the effect ofhaving a pupil diameter of less than 2.6 mm in the eye that receivedsaid dosage when measured under photopic conditions. In certainembodiments, as a result of the administering, the patient experiencesthe effect of having a pupil diameter of less than 2.4 mm in the eyethat received said dosage when measured under photopic conditions. Incertain embodiments, as a result of the administering, the patientexperiences the effect of having a pupil diameter of less than 2.2 mm inthe eye that received said dosage when measured under photopicconditions. In certain embodiments, the patient experiences the effectof having a pupil diameter of less than 2 mm in the eye that receivedsaid dosage when measured under photopic conditions. In certainembodiments, as a result of the administering, the patient experiencesthe effect of having a pupil diameter of less than 1.9 mm in the eyethat received said dosage when measured under photopic conditions. Incertain embodiments, as a result of the administering, the patientexperiences the effect of having a pupil diameter of less than 1.8 mm inthe eye that received said dosage when measured under photopicconditions. In certain embodiments, as a result of the administering,the patient experiences the effect of having a pupil diameter of lessthan 1.7 mm in the eye that received said dosage when measured underphotopic conditions. In certain embodiments, as a result of theadministering, the patient experiences the effect of having a pupildiameter of less than 1.6 mm in the eye that received said dosage whenmeasured under photopic conditions.

In certain embodiments, the patient experiences said effect for aduration of at least 6 hours. In certain embodiments, the patientexperiences said effect for a duration of at least 12 hours. In certainembodiments, the patient experiences said effect for a duration of atleast 18 hours. In certain embodiments, the patient experiences saideffect for a duration of at least 20 hours. In certain embodiments, thepatient experiences said effect for a duration of at least 24 hours. Incertain embodiments, the patient experiences said effect for a durationof at least 30 hours. In certain embodiments, the patient experiencessaid effect for a duration of at least 48 hours.

Reduction in Intraocular Pressure

Another benefit that may be experienced by patients is a reduction inintraocular pressure in an eye that receives an alpha-adrenergicantagonist.

I. General Considerations for Therapeutic Methods

General considerations that may be applied to therapeutic methodsdescribed herein (e.g., the methods described in Parts A-H above) areprovided below and include, for example, the identity of thealpha-adrenergic antagonist, the dosage of alpha-adrenergic antagonist,the formulation of the dosage, and patient populations that may deriveparticular benefits from the therapeutic methods. A more thoroughdescription of such features is provided below. The invention embracesall permutations and combinations of these features.

Identity of the Alpha-Adrenergic Antagonist

The methods may be further characterized according to the identity ofthe alpha-adrenergic antagonist. For example, in certain embodiments,the alpha-adrenergic antagonist is phentolamine, phenoxybenzamine,tolazoline, trazodone, alfuzosin, doxazosin, prazosin, tamsulosin,terazosin, silodosin, atipamezole, idazoxan, mirtazapine, yohimbine,fenoldopam, thymoxamine, or a pharmaceutically acceptable salt of any ofthe foregoing. In certain embodiments, the alpha-adrenergic antagonistis phentolamine or a pharmaceutically acceptable salt thereof. Incertain embodiments, the alpha-adrenergic antagonist is apharmaceutically acceptable salt of phentolamine. In certainembodiments, the alpha-adrenergic antagonist is phentolamine mesylate.In certain other embodiments, the alpha-adrenergic antagonist isfenoldopam or a pharmaceutically acceptable salt thereof. In certainembodiments, the alpha-adrenergic antagonist is fenoldopam mesylate.

In certain embodiments, the alpha-adrenergic antagonist is anon-selective alpha-adrenergic antagonist. In certain embodiments, thealpha-adrenergic antagonist is a reversible, non-selectivealpha-adrenergic antagonist.

In certain embodiments, the alpha-adrenergic antagonist is characterizedaccording to its activity towards certain alpha-adrenergic receptors.Accordingly, in certain embodiments, the alpha-adrenergic antagonist hasantagonist activity towards an alpha-1 adrenergic receptor. Activitytoward the alpha-1 adrenergic receptor may be further characterizedaccording to whether there is activity toward one or more of the alpha-1adrenergic receptor subtypes (e.g., alpha-1A, alpha-1B, and alpha-1D).Accordingly, in certain embodiments, the alpha-adrenergic antagonist hasantagonist activity towards the alpha-1A adrenergic receptor. In certainembodiments, the alpha-adrenergic antagonist has antagonist activitytowards the alpha-1B adrenergic receptor. In certain embodiments, thealpha-adrenergic antagonist has antagonist activity towards the alpha-1Dadrenergic receptor. In certain embodiments, the alpha-adrenergicantagonist has antagonist activity towards each of the alpha-1adrenergic receptor subtypes.

In certain embodiments, the alpha-adrenergic antagonist has antagonistactivity towards an alpha-2 adrenergic receptor. Activity toward thealpha-2 adrenergic receptor may be further characterized according towhether there is activity toward one or more of the alpha-2 adrenergicreceptor subtypes (e.g., alpha-2A, alpha-2B, and alpha-2C). Accordingly,in certain embodiments, the alpha-adrenergic antagonist has antagonistactivity towards the alpha-2A adrenergic receptor. In certainembodiments, the alpha-adrenergic antagonist has antagonist activitytowards the alpha-2B adrenergic receptor. In certain embodiments, thealpha-adrenergic antagonist has antagonist activity towards the alpha-2Cadrenergic receptor. In certain embodiments, the alpha-adrenergicantagonist has antagonist activity towards each of the alpha-2adrenergic receptor subtypes.

The alpha-adrenergic antagonist may be characterized according to itsactivity towards (i) an alpha-1 adrenergic receptor versus (ii) analpha-2 adrenergic receptor. In certain embodiments, thealpha-adrenergic antagonist has antagonist activity at both (i) analpha-1 adrenergic receptor and (ii) an alpha-2 adrenergic receptor. Incertain embodiments, the alpha-adrenergic antagonist has antagonistactivity at (i) an alpha-1 adrenergic receptor but not (ii) an alpha-2adrenergic receptor. In certain embodiments, the alpha-adrenergicantagonist has antagonist activity at (i) an alpha-2 adrenergic receptorbut not (ii) an alpha-1 adrenergic receptor. In certain embodiments, theinhibitory activity (as, for example, measured by an IC₅₀ value) of thealpha-adrenergic antagonist is at least 10-fold greater towards (i) thealpha-1 adrenergic receptor compared to the (ii) alpha-2 adrenergicreceptor. In certain embodiments, the inhibitory activity (as, forexample, measured by an IC₅₀ value) of the alpha-adrenergic antagonistis at least 10-fold greater towards (i) the alpha-2 adrenergic receptorcompared to (ii) the alpha-1 adrenergic receptor.

Dosage of Alpha-Adrenergic Antagonist

The methods may be further characterized according to the dosage of thealpha-adrenergic antagonist. For example, in certain embodiments, thedosage of alpha-adrenergic antagonist is less than about 2 mg. Incertain embodiments, the dosage of alpha-adrenergic antagonist is lessthan about 1.5 mg. In certain embodiments, the dosage ofalpha-adrenergic antagonist is less than about 1 mg. In certainembodiments, the dosage of alpha-adrenergic antagonist is less thanabout 0.5 mg.

Dosage of Phentolamine or Pharmaceutically Acceptable Salt Thereof

When the alpha-adrenergic antagonist is phentolamine or apharmaceutically acceptable salt thereof, the methods may be furthercharacterized according to the amount of phentolamine orpharmaceutically acceptable salt thereof in the dosage. For example, incertain embodiments, the dosage contains from about 0.1 mg to about 2.0mg of phentolamine or a pharmaceutically acceptable salt thereof. Incertain embodiments, the dosage contains from about 0.5 mg to about 1.0mg of phentolamine or a pharmaceutically acceptable salt thereof.

In certain other embodiments, the dosage contains from about 0.1 mg toabout 2.0 mg of phentolamine mesylate. In certain embodiments, thedosage contains from about 0.2 mg to about 0.7 mg of phentolaminemesylate. In certain embodiments, the dosage contains about 0.25 mg ofphentolamine mesylate. In certain other embodiments, the dosage containsfrom about 0.4 mg to about 0.6 mg of phentolamine mesylate. In certainembodiments, the dosage contains about 0.5 mg of phentolamine mesylate.In certain other embodiments, the dosage contains from about 0.8 mg toabout 1.2 mg of phentolamine mesylate. In certain embodiments, thedosage contains about 1 mg of phentolamine mesylate.

The dosage of phentolamine or a pharmaceutically acceptable salt thereofis desirably administered to the eye of the patient in the form of anophthalmic solution, which is delivered to the eye in the form of an eyedrop. In certain embodiments, the dosage is administered as one eyedrop. A standard eye drop typically contains from about 0.03 mL to about0.05 mL of solution. Preferably, an eye drop contains about 0.05 mL ofsolution.

In certain embodiments, the dosage may be in the form of an ophthalmicsolution. For example, in certain embodiments, the dosage is anophthalmic solution containing an aqueous pharmaceutically acceptablecarrier and phentolamine or a pharmaceutically acceptable salt thereof.In certain embodiments, the dosage is an ophthalmic solution containingwater, a polyol, and phentolamine or a pharmaceutically acceptable saltthereof. In certain embodiments, the dosage is an ophthalmic solutioncontaining water, a polyol, an alkali metal carboxylate, andphentolamine or a pharmaceutically acceptable salt thereof.

In certain other embodiments, the dosage is an ophthalmic solutioncontaining an aqueous pharmaceutically acceptable carrier andphentolamine mesylate. In certain embodiments, the dosage is anophthalmic solution containing water, mannitol, and phentolaminemesylate. In certain embodiments, the dosage is an ophthalmic solutioncontaining water, mannitol, sodium acetate, and phentolamine mesylate.

In certain other embodiments, the dosage is an aqueous ophthalmicsolution free of a chelating agent containing:

-   -   (a) about 0.1% (w/v) to about 2% (w/v) of phentolamine mesylate;    -   (b) about 1% (w/v) to about 6% (w/v) of at least one polyol        compound selected from the group consisting of mannitol,        glycerol, and propylene glycol;    -   (c) about 1 mM to about 6 mM of an alkali metal acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4 to 6 and            does not contain a chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutionfree of a chelating agent containing:

-   -   (a) about 0.5% (w/v) to about 2% (w/v) of phentolamine mesylate;    -   (b) about 1% (w/v) to about 6% (w/v) of at least one polyol        compound selected from the group consisting of mannitol,        glycerol, and propylene glycol;    -   (c) about 1 mM to about 6 mM of an alkali metal acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.5 to 5.5 and            does not contain a chelating agent.

In certain embodiments, the at least one polyol is mannitol. In certainembodiments, the solution contains 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainembodiments, the solution comprises 3 mM sodium acetate.

In certain embodiments, the dosage is an aqueous ophthalmic solutionfree of a chelating agent containing:

-   -   (a) about 0.25% (w/v) to about 2% (w/v) of phentolamine        mesylate;    -   (b) about 3% (w/v) to about 5% (w/v) of mannitol;    -   (c) about 2 mM to about 4 mM of sodium acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.5 to 5.2 and            does not contain a chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutionfree of a chelating agent containing:

-   -   (a) about 0.5% (w/v) to about 2% (w/v) of phentolamine mesylate;    -   (b) about 3% (w/v) to about 5% (w/v) of mannitol;    -   (c) about 2 mM to about 4 mM of sodium acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.6 to 5.2 and            does not contain a chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutionfree of a chelating agent containing:

-   -   (a) about 0.5% (w/v) to about 1% (w/v) of phentolamine mesylate;    -   (b) about 4% mannitol;    -   (c) about 3 mM sodium acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.6 to 5.2 and            does not contain a chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutioncontaining:

-   -   (a) about 0.25% (w/v) to about 2% (w/v) of phentolamine        mesylate;    -   (b) about 3% (w/v) to about 5% (w/v) of mannitol;    -   (c) about 1 mM to about 6 mM of sodium acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.5 to 5.2 and            does not contain any additional component that is a            chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutioncontaining:

-   -   (a) about 1% (w/v) of phentolamine mesylate;    -   (b) about 3% (w/v) to about 5% (w/v) of mannitol;    -   (c) about 2 mM to about 4 mM of a buffer comprising sodium        acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.5 to 5.2 and            does not contain any additional component that is a            chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutioncontaining:

-   -   (a) about 0.25% (w/v) to about 2% (w/v) of phentolamine        mesylate;    -   (b) about 3% (w/v) to about 5% (w/v) of mannitol;    -   (c) about 2 mM to about 4 mM of sodium acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.5 to 5.2 and            does not contain any additional component that is a            chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutioncontaining:

-   -   (a) about 0.5% (w/v) to about 2% (w/v) of phentolamine mesylate;    -   (b) about 3% (w/v) to about 5% (w/v) of mannitol;    -   (c) about 2 mM to about 4 mM of a buffer comprising sodium        acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.6 to 5.2 and            does not contain any additional component that is a            chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutioncontaining:

-   -   (a) about 0.5% (w/v) to about 1% (w/v) of phentolamine mesylate;    -   (b) about 4% mannitol;    -   (c) about 3 mM of a buffer comprising sodium acetate; and    -   (d) water;        -   wherein the solution has a pH in the range of 4.6 to 5.2 and            does not contain any additional component that is a            chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutioncomprising: (a) about 1% (w/v) of phentolamine mesylate; (b) about 4%(w/v) mannitol; (c) about 3 mM of a buffer comprising sodium acetate;and (d) water; wherein the solution has a pH in the range of 4.5 to 5.5and does not contain any additional component that is a chelating agent.

In certain embodiments, the dosage is an aqueous ophthalmic solutionfree of a chelating agent comprising: (a) about 1% (w/v) of phentolaminemesylate; (b) about 4% (w/v) mannitol; (c) about 3 mM of a buffercomprising sodium acetate; and (d) water; wherein the solution has a pHin the range of 4.0 to 7.5 and does not contain a chelating agent.

Combination Therapy Dosing Considerations

In embodiments where more than one therapeutic agent is administered,the amount of each therapeutic agent and the relative timing ofadministration of each therapeutic agent may be selected in order toachieve a desired combined therapeutic effect. For example, whenadministering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously, and the like.

In certain embodiments, the therapeutic agents may act additively orsynergistically. A synergistic combination may allow the use of lowerdosages of one or more agents and/or less frequent administration of oneor more agents of a combination therapy. A lower dosage or less frequentadministration of one or more agents may lower toxicity of the therapywithout reducing the efficacy of the therapy.

Patient Populations that May Derive Particular Benefits from theTherapeutic Methods

The methods may be further characterized according to patientpopulations that may derive particular benefits from the therapeuticmethods. For example, in certain embodiments, the patient is a human. Incertain embodiments, the patient is an adult human. In certainembodiments, the patient is a geriatric human. In certain embodiments,the patient is a pediatric human.

Time of Administration

Various methods described above require administration of the dosage ator near the bedtime of the patient. Accordingly, in certain embodiments,the dosage is administered within 2 hours, 1.5 hours, 1 hour, 45minutes, 30 minutes, or 15 minutes of the patient's bedtime. In certainembodiments, the dosage is administered within 1 hour of the patient'sbedtime.

Administering an Agent that Reduces Eye Redness

The methods may be further characterized according to whether or not anagent that reduces eye redness is administered to the eye of thepatient. In certain embodiments, the method further comprisesadministering to the eye of the patient an effective amount of an agentreduces eye redness. Exemplary agents that reduce eye redness arebrimonidine, tetrahydrozoline, oxymetazoline, naphthazoline, or apharmaceutically acceptable salt thereof. These agents are not expectedto alter pupil diameter. In certain embodiments, the agent that reduceseye redness is brimonidine or a pharmaceutically acceptable salt thereof(e.g., brimonidine tartrate). Brimonidine tartrate is marketed asLUMIFY® (which is an ophthalmic solution containing brimonidine tartrate(0.025% w/w)). In certain embodiments, the agent that reduces eyeredness is oxymetazoline or a pharmaceutically acceptable salt thereof.An ophthalmic solution containing oxymetazoline is commerciallyavailable as VISINE L.R.®. In certain embodiments, the agent thatreduces eye redness is naphthazoline or a pharmaceutically acceptablesalt thereof, such as naphthazoline hydrochloride, which is marketedcommercially as CLEAR EYES®.

Improvement in Visual Performance

One benefit of the therapeutic methods is that the patient mayexperience an improvement in visual performance. Visual performancepertains to the patient's overall vision quality and includes apatient's ability to see clearly, as well as ability to distinguishbetween an object and its background.

One aspect of visual performance is visual acuity. Visual acuity is ameasure of a patient's ability to see clearly. Visual acuity can bemeasured using, for example, a Snellen chart. Further, the visual acuitymeasurement can be taken under scotopic conditions, mesopic conditions,and/or photopic conditions.

Another aspect of visual performance is contrast sensitivity. Contrastsensitivity is a measure of the patient's ability to distinguish betweenan object and its background. Contrast sensitivity can be measuredusing, for example, a Holladay Automated Contrast Sensitivity System.The contrast sensitivity can be measured under various light conditions,including, for example, photopic conditions, mesopic conditions, andscotopic conditions, each either with or without glare. In certainembodiments, the contrast sensitivity is measured under mesopicconditions either with or without glare.

In certain embodiments, the improvement in visual performance providedby the method is improved visual acuity. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under scotopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under photopic conditions. In certain embodiments, theimprovement in visual acuity is a three-line improvement in thepatient's vision as measured using a vision chart. In certainembodiments, the improvement in visual acuity is a two-line improvementin the patient's vision as measured using a vision chart. In certainother embodiments, the improvement in visual acuity is a one-lineimprovement in the patient's vision as measured using a vision chart. Incertain embodiments, the vision chart is a Snellen chart. In certainother embodiments, the vision chart is a Jaeger chart. In certain otherembodiments, the vision chart is a Rosenbaum chart or a ETDRS chart. Incertain embodiments, the improvement in visual acuity is measured at anear distance (e.g., about 1, 2, or 3 feet). In certain embodiments, theimprovement in visual acuity is measured at a far distance (e.g., about20, 25, or 30 feet). In certain embodiments, the improvement in visualacuity is an improvement in near-vision visual acuity. In certainembodiments, the improvement in visual acuity is an improvement indistance visual acuity. In certain embodiments, the improvement invisual acuity is (i) an improvement in near-vision visual acuity and(ii) an improvement in distance visual acuity.

In certain embodiments, the improvement in visual performance providedby the method is improved contrast sensitivity. The improvement incontrast sensitivity can be measured under various light conditions,such as photopic conditions, mesopic conditions, and scotopicconditions. In certain embodiments, the improvement in visualperformance provided by the method is improved contrast sensitivityunder photopic conditions. In certain embodiments, the improvement invisual performance provided by the method is improved contrastsensitivity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedcontrast sensitivity under scotopic conditions. Further, contrastsensitivity can be measured in the presence of glare or the absence ofglare. All combinations of light conditions and glare are contemplated.

Benefits provided by the therapeutic methods can be characterizedaccording to the patient's improvement in contrast sensitivity. Forexample, in certain embodiments, the improvement in contrast sensitivityis at least a 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measuredunder mesopic conditions using the Holladay Automated ContrastSensitivity System. In certain embodiments, the improvement in contrastsensitivity is at least a 10% (or 20%, 30%, 50%, 60%, or 70%)improvement measured under photopic conditions using the HolladayAutomated Contrast Sensitivity System. In certain other embodiments, theimprovement in contrast sensitivity is at least a 10% (or 20%, 30%, 50%,60%, or 70%) improvement measured under mesopic conditions or scotopicconditions using the Holladay Automated Contrast Sensitivity System. Incertain other embodiments, the improvement in contrast sensitivity ismeasured using a Pelli-Robson Contrast Sensitivity Chart.

In certain other embodiments, the improvement in visual performanceprovided by the method is both (i) improved visual acuity (such as underscotopic conditions, mesopic conditions, and/or photopic conditions) and(ii) improved contrast sensitivity (such as under scotopic conditions,mesopic conditions, and/or photopic conditions).

In certain other embodiments, the improvement in visual performance ischaracterized according to one or more of the following:

-   -   assessment of uncorrected near visual acuity (e.g., a binocular        assessment of uncorrected near visual acuity);    -   average change from Baseline in Uncorrected Near Visual Acuity        (UNVA); or    -   proportion of subjects with at least a 3 line (e.g., 15 letter)        improvement in the study eye in the measurement of        post-treatment monocular best-corrected distance visual acuity        at 45 cm compared to baseline monocular best-corrected distance        visual acuity at 45 cm post treatment.

In certain other embodiments, the improvement in visual performance ischaracterized according to one or more of the following:

-   -   assessment of uncorrected near visual acuity (e.g., a binocular        assessment of uncorrected near visual acuity);    -   average change from Baseline in Uncorrected Near Visual Acuity        (UNVA, binocular); or    -   proportion of subjects with at least a 3 line (e.g., 15 letter)        improvement in the study eye in the measurement of        post-treatment monocular best-corrected distance visual acuity        at 35 cm compared to baseline monocular best-corrected distance        visual acuity at 35 cm post treatment.

Reduction in Pupil Diameter

One benefit of the therapeutic methods is that the patient mayexperience a reduction in pupil diameter. Reduction in pupil diametercan result in improvement in visual performance.

The reduction in pupil diameter may be characterized according to thepercent reduction in pupil diameter due to administering thealpha-adrenergic antagonist, such as where the reduction in pupildiameter is at least 5%, 10%, 15%, 20%, 30%, or 40%. In certainembodiments, the reduction in pupil diameter is in the range of fromabout 10% to about 40% compared to the pupil diameter of the patientunder the same conditions but not having received the therapy defined bythe method. In certain embodiments, the reduction in pupil diameter isin the range of from about 20% to about 30% compared to the pupildiameter of the patient under the same conditions but not havingreceived the therapy defined by the method. In certain embodiments, thereduction in pupil diameter is in the range of from about 20% to about40% compared to the pupil diameter of the patient under the sameconditions but not having received the therapy defined by the method. Incertain embodiments, the reduction in pupil diameter is measured underphotopic conditions.

In a more specific embodiment, the reduction in pupil diameter can becharacterized according to, for example, the percent reduction in pupildiameter and size of the pupil measured under certain light conditions.Accordingly, in certain embodiments, the reduction in pupil diameterunder mesopic conditions is at least 5% compared to the pupil diameterof the patient under the same mesopic conditions but not having receivedthe therapy defined by the method. In certain other embodiments, thereduction in pupil diameter under mesopic conditions is at least 10%compared to the pupil diameter of the patient under the same mesopicconditions but not having received the therapy defined by the method. Incertain other embodiments, the reduction in pupil diameter under mesopicconditions is at least 20% compared to the pupil diameter of the patientunder the same mesopic conditions but not having received the therapydefined by the method. In certain other embodiments, the reduction inpupil diameter under mesopic conditions is at least 30% compared to thepupil diameter of the patient under the same mesopic conditions but nothaving received the therapy defined by the method. In certain otherembodiments, the patient experiences a reduction in pupil diameter of atleast 0.5 mm when measured under mesopic conditions relative to thediameter of the patient's pupil under the same mesopic conditions butnot having received the therapy defined by the method. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm,or about 0.6 mm to about 2 mm when measured under mesopic conditionsrelative to the diameter of the patient's pupil under the same mesopicconditions but not having received the therapy defined by the method. Incertain other embodiments, the patient experiences a reduction in pupildiameter ranging from about 0.6 mm to about 1.2 mm when measured undermesopic conditions relative to the diameter of the patient's pupil underthe same mesopic conditions but not having received the therapy definedby the method. In yet other embodiments, the patient's pupil is reducedto a diameter of about 3 mm to about 5 mm, about 3 mm to about 6 mm,about 4 mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm toabout 7 mm under mesopic conditions due to the therapy defined by themethod. In certain embodiments, the patient's pupil is reduced to adiameter of about 4 mm to about 6 mm under mesopic conditions due to thetherapy defined by the method.

In certain embodiments, the reduction in pupil diameter under photopicconditions is at least 5% compared to the pupil diameter of the patientunder the same photopic conditions but not having received the therapydefined by the method. In certain other embodiments, the reduction inpupil diameter under photopic conditions is at least 10% compared to thepupil diameter of the patient under the same photopic conditions but nothaving received the therapy defined by the method. In certain otherembodiments, the reduction in pupil diameter under photopic conditionsis at least 20% compared to the pupil diameter of the patient under thesame photopic conditions but not having received the therapy defined bythe method. In certain other embodiments, the reduction in pupildiameter under photopic conditions is at least 30% compared to the pupildiameter of the patient under the same photopic conditions but nothaving received the therapy defined by the method. In certain otherembodiments, the patient experiences a reduction in pupil diameter of atleast 0.5 mm when measured under photopic conditions relative to thediameter of the patient's pupil under the same photopic conditions butnot having received the therapy defined by the method. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm,or about 0.6 mm to about 2 mm when measured under photopic conditionsrelative to the diameter of the patient's pupil under the same photopicconditions but not having received the therapy defined by the method. Incertain other embodiments, the patient experiences a reduction in pupildiameter ranging from about 0.6 mm to about 1.2 mm when measured underphotopic conditions relative to the diameter of the patient's pupilunder the same photopic conditions but not having received the therapydefined by the method. In yet other embodiments, the patient's pupil isreduced to a diameter of about 3 mm to about 5 mm, about 3 mm to about 6mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm toabout 7 mm under photopic conditions due to the therapy defined by themethod. In certain embodiments, the patient's pupil is reduced to adiameter of about 4 mm to about 6 mm under photopic conditions due tothe therapy defined by the method.

Reduction in pupil diameter can be analyzed and characterized usingprocedures such as those described below in which a phentolaminemesylate solution was administered to patients' eyes and change in pupildiameter was measured and characterized. This was performed in thecontext of a clinical study using patients that were at least 18 yearsold and had a clinical history of pupil sizes of at least 7 mm indiameter under dim light conditions. The phentolamine mesylate solutioncontained either 0.2% (w/v) phentolamine mesylate, 0.4% (w/v)phentolamine mesylate, or 0.8% (w/v) phentolamine mesylate.

Part I— Experimental Procedures

Sixteen patients were randomized into four groups (of four subjectseach). Each group was treated on three successive study visits separatedby at least 4 days with one drop of ophthalmic oxymetazoline solution(Visine LR®) in each eye followed by one drop test article in each eye.The test article was a 0.2% (w/v) phentolamine mesylate solution, 0.4%(w/v) phentolamine mesylate solution, 0.8% (w/v) phentolamine mesylatesolution, or placebo. Test articles contained the designed amount ofphentolamine mesylate in a solution of Tears Naturale II® (from AlconLabs). Placebo was just Tears Naturale II® (from Alcon Labs). TearsNaturale II® (from Alcon Labs) contains Dextran 70 (0.1% by weight),Hydroxypropyl Methylcellulose 2910 (0.3% by weight), Polyquatemium-1(0.001% by weight), potassium chloride, water (purified), sodium borate,sodium chloride, and hydrochloric acid and/or sodium hydroxide asnecessary to adjust the pH. The patients' pupil diameters were recordedat baseline (i.e., prior to treatment administration), and at 30minutes, 1 hour, 2 hours, 4 hours, and 8 hours after administration oftest articles. Total study duration was approximately nine hours.Treatment group randomization schedules are provided in Table 1 below.

TABLE 1 TREATMENT GROUP RANDOMIZATION SCHEDULES Visit 1 Treatment Visit2 Treatment Visit 3 Treatment Group 1 (N = 4) 0.2% (w/v) 0.4% (w/v) 0.8%(w/v) phentolamine phentolamine phentolamine mesylate solution mesylatesolution mesylate solution Group 2 (N = 4) 0.2% (w/v) 0.4% (w/v) placebophentolamine phentolamine mesylate solution mesylate solution Group 3 (N= 4) 0.2% (w/v) placebo 0.8% (w/v) phentolamine phentolamine mesylatesolution mesylate solution Visit 1 Treatment Visit 2 Treatment Visit 3Treatment Group 4 (N = 4) placebo 0.4% (w/v) 0.8% (w/v) phentolaminephentolamine mesylate solution mesylate solution

Patients were eligible for enrollment if they were (a) at least 18 yearsof age, and (b) had a documented pupil size in dim light of greater than7 mm. Patients were ineligible for enrollment in the study if they metany of the following criteria: (a) had moderate to severe hypertension,(b) had a history of heart rate abnormalities, (c) had been administeredany investigational drug within 14 days of screening, (d) had a knownlocal or systemic hypersensitivity to adrenergic antagonists, or (e) hadcentral corneal pathology.

Pupil diameters were measured to within 0.1 mm for each eye at baselineand each subsequent time point using a NeurOptics™ pupilometer.Comparisons of changes in mean values within treatment groups weretested for significance using two-tailed paired two sample t-tests witha threshold for significance set at p<0.01 (Bonferroni Correction formultiple paired t-tests). Differences between treatment groups withrespect to mean values for pupil size over the course of the study weretested for significance using repeated measure ANOVA (which discardsdata from subjects lacking any data points). Differences in meansbetween treatment groups at individual time points were tested forsignificance using one-way ANOVA. If one-way ANOVA showed significanceat a given time point, ad hoc Fisher's testing was performed to identifysignificant differences between individual group means.

Part II Results

Fifteen of 16 patients completed the study. One patient randomized toGroup 3 completed only two of three clinic visits, missing the 0.8%(w/v) phentolamine mesylate dose. The results of pupil measurements aredescribed below.

One criterion for entrance into the study was historical documentationof a pupil size >7 mm when measured under dim light conditions. Table 2provides the mean pupil diameters, standard deviation of pupildiameters, and the observed range of diameters recorded immediatelyprior to administration of each treatment.

TABLE 2 BASELINE PUPIL MEASURES 0.2% (w/v) 0.4% (w/v) 0.8% (w/v)Phentolamine Phentolamine Phentolamine Pupil Variable Placebo MesylateMesylate Mesylate Sample Size^(a) 24 24 24 22^(b) Mean Diameter (mm) 7.87.8 7.7 8.0 Standard Deviation (mm) 0.6 0.9 0.7 1.1 Range (mm) 6.5-8.75.2-8.8 5.8-8.6 4.6-9.3 ^(a)—measurements from each pupil treatedseparately ^(b)—one subject missed the 0.8% phentolamine dosing visit

Average baseline pupil diameters were comparable across all fourtreatment groups, with observed differences in means (Table 2) notstatistically significant (P=0.766). Of the 94 baseline pupil diameterscollected during the study, there were twelve instances (representing 3subjects; Table 3) in which baseline pupil diameters were less than theinclusion criterion of 7 mm. Baseline pupil diameters less than 7 mmwere evenly distributed between treatment groups (2, 3, 4, and 3 pupilsin Placebo, 0.2%, 0.4%, and 0.8% (w/v) phentolamine mesylate treatmentgroups, respectively).

TABLE 3 SUBJECTS WITH BASELINE PUPIL DIAMETERS LESS THAN 7 MM Subject 2Subject 6 Subject 16 Study Right Pupil Left Pupil Right Pupil Left PupilRight Pupil Left Pupil Visit (mm) (mm) (mm) (mm) (mm) (mm) 1 6.7 7.1 7 75.8 5.7 2 6.7 6.5 6.8 6.3 6.3 5.8 3 7.9 8.2 7.4 6.7 5.5 4.6

For all study groups, mean pupil diameters were relatively unchanged at30 minutes after treatment. By one hour post treatment, mean pupildiameters were lower (P=0.47) for phentolamine-treated subjects. Meanpupil diameters for subjects receiving placebo were relatively constantfor the 8 hours of post-treatment observation.

TABLE 4 MEAN PUPIL DIAMETERS DURING THE STUDY 30 1 2 4 8 TreatmentGroup^(a) Baseline min hour hours hours hours Placebo Mean Diameter (mm)7.83 7.87 7.80 7.93 7.87 8.08^(b) Standard Deviation 0.61 0.81 0.79 0.600.58 0.75 Minimum (mm) 6.5 5.5 5.9 6.5 6.8 6.5 Maximum (mm) 8.7 9.0 9.29.0 9.0 9.3 0.2% (w/y) Phentolamine Mesylate Mean Diameter (mm) 7.787.74 7.54 7.01^(c) 7.30^(d) 7.18 Standard Deviation 0.88 1.02 1.02 0.820.51 0.90 Minimum (mm) 5.2 5.1 4.9 4.7 6.3 4.7 Maximum (mm) 8.8 9.2 8.98.4 8.0 8.5 0.4% (w/y) Phentolamine Mesylate Mean Diameter (mm) 7.717.72 7.41 7.05 7.01 7.01 Standard Deviation 0.71 0.81 0.77 0.84 0.920.97 Minimum (mm) 5.8 5.6 5.5 5.0 5.0 4.8 Maximum (mm) 8.6 8.8 8.3 8.48.1 8.6 0.8% (w/y) Phentolamine Mesylate^(e) Mean Diameter (mm) 7.967.87 7.69 7.30 7.32 7.40 Standard Deviation 1.10 0.97 0.97 0.99 0.990.99 Minimum (mm) 4.6 5.2 5.1 4.7 5.5 4.7 Maximum (mm) 9.3 9.2 9.1 8.78.6 8.7 ^(a)24 pupils per sample except where noted ^(b)20 pupils; 8hour data for subjects 2 and 11, visit 2, were not recorded ^(c)22pupils; 2 hour data from subject 7, visit 1 not recorded ^(d)22 pupils;4 hour data from subject 16, visit 1 not recorded ^(e)22 pupils at eachtime point, subject 16 missed visit 3

Repeated measures ANOVA showed a significant (p<0.001) differencebetween treatment groups with respect to pupil diameter over the courseof the study. Significant differences in mean pupil diameters betweentreatment were identified by one-way ANOVA at 2 hours (p=0.0006), 4hours (p=0.0027) and 8 hours (p=0.0016) after treatment. Ad hoc Fisher'stests of significance between individual group means demonstratedsignificant differences in mean pupil diameters of subjects treated withany concentration of phentolamine mesylate when compared to placebo at2, 4 and 8 hours (Table 5). In contrast, there were no statisticallysignificant differences in mean pupil diameters observed betweendifferent doses of phentolamine at any time point.

TABLE 5 SIGNIFICANCE OF DIFFERENCES BETWEEN MEAN PUPIL DIAMETERSTreatment Comparison 2 hours 4 hours 8 hours Placebo vs. 0.2% (w/v) P =0.0003 P = 0.0147 P = 0.0018 Phentolamine Mesylate Placebo vs. 0.4%(w/v) P = 0.0003 P = 0.0002 P = 0.0002 Phentolamine Mesylate Placebo vs.0.8% (w/v) P = 0.0110 P = 0.0200 P = 0.0199 Phentolamine Mesylate*—Fishe's Ad Hoc test of means for time points previously shown to besignificant by One-Way ANOVA

For all treatment groups, mean pupil diameters were relatively unchangedfrom baseline at 30 minutes after treatment (Table 6). By one hour posttreatment, change from baseline in mean pupil diameters was significant(p<0.01) for subjects treated with 0.2% (w/v), 0.4% (w/v), and 0.8%(w/v) phentolamine mesylate. Mean pupil diameters did not significantlychange from baseline for subjects receiving placebo over the 8 hours ofpost-treatment observation.

Differences in mean pupil diameters of treatment groups are expressed asmean changes in diameter from baseline in Table 6. When mean changes inpupil diameters from baseline are evaluated as a function of time, it isapparent that those subjects receiving phentolamine mesylate experiencedsignificant reductions in pupil size over the course of the study.

TABLE 6 MEAN PUPIL DIAMETER CHANGES FROM BASELINE OVER TIME 30 1 2 4 8Treatment Group min hour hours hours hours Placebo Mean Change (mm) 0.04−0.03 0.10 0.04 0.12 Standard Deviation 0.32 0.36 0.34 0.51 0.35 SampleSize (pupils) 24 24 24 24 20 P-value^(a) 0.57 0.66 0.15 0.72 0.15 0.2%(w/v) Phentolamine Mesylate Mean Change (mm) −0.04 −0.24 −0.75 −0.69−0.59 Standard Deviation 0.33 0.37 0.51 0.49 0.62 Sample Size (pupils)24 24 22 22 24 P-value^(a) 0.58 <0.005 <0.001 <0.001 <0.001 0.4% (w/v)Phentolamine Mesylate Mean Change (mm) 0.00 −0.29 −0.64 −0.74 −0.74Standard Deviation 0.40 0.33 0.46 0.45 0.47 Sample Size (pupils) 22 2222 22 22 P-value^(a) 0.86 <0.001 <0.001 <0.001 <0.001 0.8% (w/v)Phentolamine Mesylate Mean Change (mm) −0.10 −0.27 −0.66 −0.64 −0.56Standard Deviation 0.31 0.43 0.44 0.61 0.43 Sample Size (pupils) 22 2222 22 22 P-value^(a) 0.16 <0.007 <0.001 <0.001 <0.001 ^(a)—Two-sidedpaired two-sample t-test. P < 0.01 is significant by Bonferronicorrection

Impact on Distance Vision Acuity in the Patient's Eye

The methods may be further characterized according to whether there isan adverse impact on distance vision acuity in the patient's eye due tothe method. In certain embodiments, distance vision acuity of thepatient is not reduced.

Administer Dosage to One or Both of the Patient's Eyes

The methods may be further characterized according to whether thealpha-adrenergic antagonist is administered to one or both of thepatient's eyes. In certain embodiments, the dosage is administered toonly one eye in the patient. In certain embodiments, the dosage isadministered to both eyes in the patient.

Reducing Aberrant Focus of Scattered Light Rays in a Patient's Eye

One benefit of the therapeutic methods is that the patient mayexperience a reduction in aberrant focus of scattered light rays in thepatient's eye. This can provide improvement in visual performance forthe patient. In certain embodiments, the therapeutic method provides areduction in aberrant focus of scattered light rays in a patient's eyefor at least twenty hours. In certain embodiments, the therapeuticmethod provides a reduction aberrant focus of scattered light rays in apatient's eye for at least twenty-four hours. In yet other embodiments,the therapeutic method provides a reduction aberrant focus of scatteredlight rays in a patient's eye for at least thirty-six hours, forty-eighthours, sixty hours, or seventy-two hours.

Implantable Ocular Device

Compositions described herein may be administered to the patient's eyevia an implantable ocular device that dispenses the composition. Theimplantable ocular device may be configured to dispense the compositionat a desired rate and/or frequency. In certain embodiments, theimplantable ocular device is a slow release insert.

III. Ophthalmic Solutions

Therapeutically active agents are desirably administered to the eye ofthe patient in the form of an ophthalmic solution. Such an ophthalmicsolution comprises one or more therapeutically active agents and apharmaceutically acceptable carrier. Desirably, the ophthalmic solutionexhibits good storage stability to permit distribution of the ophthalmicsolution through normal distribution channels for pharmaceuticals. Incertain embodiments, the pharmaceutically acceptable carrier is water.Additional components may be added to the ophthalmic solution in orderto optimize performance properties of the ophthalmic solution. Exemplaryadditional components include, for example, a chelating agent (e.g.,EDTA), polyol compound, poly(C₂₋₄alkylene)glycol polymer, dextran,cellulose agent, buffer, tonicity modifier, preservative, antioxidant,viscosity modifying agent, corneal permeation enhancing agent,solubilizing agent, stabilizing agent, surfactant, demulcent polymer,wetting agent, and other materials.

Ophthalmic solutions may be further characterized according to thepresence or absence of one or more of a chelating agent (e.g., EDTA),polyol compound, poly(C₂₋₄alkylene)glycol polymer, dextran, celluloseagent, buffer, tonicity modifier, preservative, antioxidant, viscositymodifying agent, corneal permeation enhancing agent, solubilizing agent,stabilizing agent, surfactant, demulcent polymer, wetting agent, andother materials. In certain embodiments, the ophthalmic solution doesnot contain a chelating agent (e.g., EDTA). In certain embodiments, theophthalmic solution does not contain a preservative. In certainembodiments, the ophthalmic solution does contain a preservative.

Various therapeutic methods above involve administering a dosage ofphentolamine or a pharmaceutically acceptable salt thereof to thepatient. The dosage of phentolamine or a pharmaceutically acceptablesalt thereof is desirably in the form of an ophthalmic solution. Theophthalmic solution is formulated to be suitable for administration tothe eye of a patient, and desirably provides immediate release ofphentolamine, that is, the ophthalmic solution is not a sustainedrelease formulation that delivers phentolamine over an extendedduration, such as hours, days or weeks.

The ophthalmic solution desirably comprises an aqueous pharmaceuticallyacceptable carrier and phentolamine or a pharmaceutically acceptablesalt thereof. The ophthalmic solution may contain excipients(s) that aresuitable for administration to the eye. Various pharmaceuticallyacceptable salts are described in the literature. The preferred saltform of phentolamine is phentolamine mesylate. Accordingly, the methodsmay use an ophthalmic solution that comprises an aqueouspharmaceutically acceptable carrier and phentolamine mesylate.

Accordingly, in certain embodiments, the dosage utilized in the methodsis an ophthalmic solution comprising an aqueous pharmaceuticallyacceptable carrier and phentolamine or a pharmaceutically acceptablesalt thereof. In certain other embodiments, the dosage is an ophthalmicsolution comprising an aqueous pharmaceutically acceptable carrier andphentolamine mesylate. In certain other embodiments, the dosage is anophthalmic solution comprising water, a polyol, and phentolamine or apharmaceutically acceptable salt thereof. In certain other embodiments,the dosage is an ophthalmic solution comprising water, mannitol, andphentolamine mesylate. In certain other embodiments, the dosage is anophthalmic solution comprising water, a polyol, an alkali metalcarboxylate, and phentolamine or a pharmaceutically acceptable saltthereof. In certain other embodiments, the dosage is an ophthalmicsolution comprising water, mannitol, sodium acetate, and phentolaminemesylate.

Other ophthalmic solutions that are contemplated for use in the presentinvention include, for example, (i) aqueous ophthalmic solutions free ofa chelating agent, and (ii) polyvinylpyrrolidone artificial tearsformulations, each of which are described in more detail below.

Ophthalmic solutions may be further characterized according to theviscosity of the solution. In certain embodiments, the ophthalmicsolution at a temperature of about 25° C. has a viscosity in the rangeof 0.9 cP to about 1.1 cP. In certain embodiments, the ophthalmicsolution at a temperature of about 25° C. has a viscosity of about 1 cP.

In certain embodiments, the ophthalmic solution comprises analpha-adrenergic antagonist (e.g., phentolamine or a pharmaceuticallyacceptable salt thereof) and one or more additional agents (e.g.,pilocarpine) described herein.

Aqueous Ophthalmic Solution Free of a Chelating Agent

In certain embodiments, the dosage utilized in the methods is an aqueousophthalmic solution free of a chelating agent, wherein said solutioncomprises (a) phentolamine or a pharmaceutically acceptable saltthereof; (b) at least one polyol compound, such as a polyol compoundhaving a molecular weight less than 250 g/mol; (c) at least one buffer;and (d) water; wherein the solution does not contain a chelating agent.The amount of ingredients in the aqueous ophthalmic solutions may beselected in order to achieve particular performance properties, such asstability to storage, minimize irritation to the eye of a patient, andenhance penetration of phentolamine into the eye of a patient.

One exemplary preferred solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.1% (w/v) to about 4% (w/v)of phentolamine or a pharmaceutically acceptable salt thereof; (b) about1% (w/v) to about 6% (w/v) of at least one polyol compound having amolecular weight less than 250 g/mol; (c) about 0.1 mM to about 10 mM ofat least one buffer; and (d) water; wherein the solution has a pH in therange of 4.0 to 7.5 and does not contain a chelating agent.

Exemplary components and features of the aqueous ophthalmic solutionsare described in more detail below.

Phentolamine & Pharmaceutically Acceptable Salts

The aqueous ophthalmic solution comprises phentolamine or apharmaceutically acceptable salt of phentolamine. Exemplarypharmaceutically acceptable salts include, for example, the hydrochloricacid salt and mesylate salt. Accordingly, in certain embodiments, thesolution comprises phentolamine (i.e., as the free base). In certainother embodiments, the solution comprises phentolamine hydrochloride. Incertain yet other embodiments, the solution comprises phentolaminemesylate.

The amount of phentolamine or a pharmaceutically acceptable salt thereofin the aqueous ophthalmic solution may be adjusted in order to achievedesired performance properties. For example, where is it desired toprovide a larger amount of phentolamine (or pharmaceutically acceptablesalt thereof) to the patient in a single administration of the aqueousophthalmic solution, the concentration of phentolamine (orpharmaceutically acceptable salt thereof) is increased in the aqueousophthalmic solution. Single administration of aqueous ophthalmicsolutions having a higher concentration of phentolamine (orpharmaceutically acceptable salt thereof) may provide the patient withreduced intraocular pressure for a longer duration of time because morephentolamine (or pharmaceutically acceptable salt thereof) isadministered to the patient.

Accordingly, in certain embodiments, the aqueous ophthalmic solutioncomprises from about 0.1% (w/v) to about 5% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain embodiments, theaqueous ophthalmic solution comprises from about 0.1% (w/v) to about 1%(w/v) of phentolamine or a pharmaceutically acceptable salt thereof,about 1% (w/v) to about 2% (w/v) of phentolamine or a pharmaceuticallyacceptable salt thereof, about 2% (w/v) to about 3% (w/v) ofphentolamine or a pharmaceutically acceptable salt thereof, about 3%(w/v) to about 4% (w/v) of phentolamine or a pharmaceutically acceptablesalt thereof, about 4% (w/v) to about 5% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain embodiments, theaqueous ophthalmic solution comprises from about 0.1% (w/v) to about 2%(w/v) of phentolamine or a pharmaceutically acceptable salt thereof. Incertain embodiments, the aqueous ophthalmic solution comprises fromabout 0.25% (w/v) to about 2% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain other embodiments,the aqueous ophthalmic solution comprises from about 0.5% (w/v) to about2% (w/v) of phentolamine or a pharmaceutically acceptable salt thereof.In certain other embodiments, the aqueous ophthalmic solution comprisesfrom about 0.25% (w/v) to about 1% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain other embodiments,the aqueous ophthalmic solution comprises about 1% (w/v) of phentolamineor a pharmaceutically acceptable salt thereof. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 0.1%(w/v) to about 4% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 0.1%(w/v) to about 2% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 2% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 0.5%(w/v) to about 2% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises about 1% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises about 0.25% (w/v) or about 0.5% (w/v) ofphentolamine mesylate.

Polyol Compounds

The aqueous ophthalmic solution comprises one or more polyol compounds.The polyol compound is an organic compound having at least two hydroxylgroups (e.g., from 2 to about 6 hydroxyl groups). The polyol compound isbeneficial to the aqueous ophthalmic solution because, for example, itcan increase the stability of the aqueous ophthalmic solution to storageand/or modify the tonicity of the aqueous ophthalmic solution. Exemplarypolyol compounds include, for example, mannitol, glycerol, propyleneglycol, ethylene glycol, sorbitol, and xylitol.

The aqueous ophthalmic solution may contain a single polyol compound ora mixture of one or more polyol compounds. In other words, the aqueousophthalmic solution comprises at least one polyol compound. In certainembodiments, the aqueous ophthalmic solution comprises at least onepolyol compound that is mannitol, glycerol, propylene glycol, ethyleneglycol, sorbitol, or xylitol. In certain other embodiments, the at leastone polyol compound is mannitol. In certain other embodiments, the atleast one polyol compound is glycerol. In certain other embodiments, theat least one polyol compound is propylene glycol. In certain otherembodiments, the at least one polyol compound is mannitol, and thesolution further comprises glycerol. In certain other embodiments, theat least one polyol compound is mannitol, and the solution furthercomprises propylene glycol. In certain other embodiments, the at leastone polyol compound is glycerol, and the solution further comprisespropylene glycol. In certain other embodiments, the mannitol describedin embodiments above is D-mannitol.

The amount of the at least one polyol compound in the aqueous ophthalmicsolution may be selected in order to achieve desired performanceproperties for the solution. The polyol compound may, for example,increase the stability of the solution to storage and/or modify thetonicity of the solution to make it more suitable for administration tothe eye of a patient. In certain embodiments, the aqueous ophthalmicsolution comprises from about 2% (w/v) to about 5% (w/v) of the at leastone polyol compound. In certain other embodiments, the aqueousophthalmic solution comprises from about 3.5% (w/v) to about 4.5% (w/v)of the at least one polyol compound. In certain other embodiments, theaqueous ophthalmic solution comprises about 4% (w/v) of the at least onepolyol compound. In certain other embodiments, the aqueous ophthalmicsolution comprises from about 2% (w/v) to about 3% (w/v) mannitol, andabout 0.5% (w/v) to about 1.5% (w/v) glycerin. In certain otherembodiments, the mannitol described in embodiments above is D-mannitol.

In certain embodiments, the amount of polyol may be selected based onthe amount of phentolamine (or pharmaceutically acceptable saltthereof), such that there is an inverse relationship between the amountof phentolamine (or pharmaceutically acceptable salt thereof) and thepolyol in order to achieve isotonicity with the eye. For example, inembodiments where the aqueous ophthalmic solution contains about 2%(w/v) phentolamine, mannitol is present in the solution at aconcentration of about 3% (w/v). In embodiments where the aqueousophthalmic solution contains about 1% (w/v) phentolamine, mannitol ispresent in the solution at a concentration of about 4% (w/v). To furtherillustrate this principle, in embodiments where the aqueous ophthalmicsolution contains about 0.5% (w/v) phentolamine, mannitol may be presentin the solution at a concentration of about 4.5% (w/v). In certainembodiments, the mannitol described in embodiments above is D-mannitol.

It is appreciated that the aqueous ophthalmic solution can containadditional ingredients described herein, such as various polymermaterials. One such embodiment is an aqueous ophthalmic solutioncomprising, for example, at least one polyol compound that is propyleneglycol, and further comprising polypropylene glycol, such aspolypropylene glycol having a weight average molecular weight in therange of about 5,000 g/mol to about 100,000 g/mol.

Poly(C₂₋₄alkylene)glycol Polymer

The aqueous ophthalmic solution may optionally comprise apoly(C₂₋₄alkylene)glycol polymer. An exemplary poly(C₂₋₄alkylene)glycolpolymer is polypropylene glycol, such as a polypropylene glycol having aweight average molecular weight in the range of about 5,000 g/mol toabout 100,000 g/mol, about 10,000 g/mol to about 50,000 g/mol, or about50,000 g/mol to about 100,000 g/mol.

Dextran

The aqueous ophthalmic solution may optionally comprise dextran. Dextranis a commercially available, branched polysaccharide comprising glucosemolecules. The amount of dextran in the aqueous ophthalmic solution maybe selected to achieve certain performance properties. In certainembodiments, the aqueous ophthalmic solution comprises from about 0.01%(w/v) to about 2% (w/v) dextran. In certain other embodiments, theaqueous ophthalmic solution comprises from about 0.01% (w/v) to about 1%(w/v) dextran.

The dextran may be further characterized according to its weight averagemolecular weight. In certain embodiments, the dextran has a weightaverage molecular weight in the range of about 65,000 g/mol to about75,000 g/mol. In certain other embodiments, the dextran has a weightaverage molecular weight of about 70,000 g/mol. In yet otherembodiments, the dextran has a weight average molecular weight in therange of about 5,000 g/mol to about 100,000 g/mol, about 10,000 g/mol toabout 50,000 g/mol, or about 50,000 g/mol to about 100,000 g/mol.

Cellulose Agent

The aqueous ophthalmic solution may optionally comprise a celluloseagent. Exemplary cellulose agents include, for example, cellulose,carboxymethyl cellulose, hydroxyethylcellulose, hydroxpropylcellulose,and hydroxypropylmethyl cellulose. In certain embodiments, the celluloseagent is hydroxypropylmethyl cellulose. In certain other embodiments,the cellulose agent is cellulose, carboxymethyl cellulose,hydroxyethylcellulose, or hydroxpropylcellulose. The amount of celluloseagent in the aqueous ophthalmic solution may be selected in order toachieve desired performance properties. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.01%(w/v) to about 2% (w/v) cellulose agent.

The cellulose agent may be further characterized according to its weightaverage molecular weight. In certain embodiments, the cellulose agenthas a weight average molecular weight in the range of about 5,000 g/molto about 100,000 g/mol, about 10,000 g/mol to about 50,000 g/mol, orabout 50,000 g/mol to about 100,000 g/mol.

Buffer

The aqueous ophthalmic solution comprises at least one buffer. Thebuffer imparts to the solution a buffering capacity, that is, thecapacity to neutralize, within limits, either acids or bases (alkali)with relatively little or no change in the original pH. The buffer maybe an acid, a base, or a combination of an acid and a base. The buffermay be organic, inorganic, or a combination of organic and inorganiccomponents. It should be understood that the buffer at least partiallydissociates in aqueous solution to form a mixture of, e.g., an acid andconjugate base or a base and conjugate acid. For example, the buffer maybe a combination of a carboxylic acid and its carboxylate salt (e.g., acombination of acetic acid and sodium acetate). In another embodiment,the buffer may be a combination of an acid and a base, where the acidand the base are not conjugates. For example, the acid may be boric acidand the base may be tris(hydroxymethyl)aminomethane (TRIS).

Exemplary buffers include organic acids (e.g., acetic acid, sorbic acid,and oxalic acid), a borate salt, a hydrogen carbonate salt, a carbonatesalt, a gluconate salt, a lactate salt, a phosphate salt, a propionatesalt, a perborate salt, tris-(hydroxymethyl)aminomethane (TRIS),bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)aminoalcohol (bis-tris),N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricene),N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine,3-(N-morpholino)propanesulfonic acid, N-(carbamoylmethyl)taurine (ACES),an amino acid, salts thereof, and combinations thereof. It should beunderstood that the salt form of a buffer may comprise any suitablecounterion. For example, the salt form of an acid may comprise an alkalior alkaline earth metal counterion.

The buffer can be characterized according to its strength, i.e., thebuffering capacity. The buffering capacity can be tested, for example,by determining the millimoles (mM) of strong acid or base (orrespectively, hydrogen or hydroxide ions) required to change the pH of abuffer solution by one unit when added to one liter (a standard unit) ofthe buffer solution. The buffering capacity generally depends on thetype and concentration of the buffer components and can be greater inparticular pH ranges. For example, a buffer may have an optimalbuffering capacity in a pH range near the pKa of the buffer, e.g.,within about 1 pH unit or within about 2 pH units of the pKa the buffer.In certain embodiments, the buffer is a weak buffer, such as an alkalimetal carboxylate (e.g., sodium acetate).

In certain embodiments, the buffer is a weak acid buffer having one ormore of the following characteristics: (a) a pKa of from about 4.0 toabout 6.0; more preferably, from about 4.5 to about 5.5; and (b) alipophilicity value Log P of from about −0.50 to about 1.5; morepreferably, from about −0.25 to about 1.35.

The amount of buffer can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. For example,in certain embodiments, the buffer may be present at a concentration ofless than about 10 mM, less than about 7 mM, less than about 5 mM, lessthan about 3 mM, or less than about 2 mM. In some embodiments, thebuffer may be present at a concentration of from about 1 mM to about 10mM, from about 1 mM to about 7 mM, from about 1 mM to about 5 mM, fromabout 1 mM to about 3 mM, from about 1 mM to about 2 mM, from about 2 mMto about 5 mM, or from about 2 mM to about 3 mM. In yet otherembodiments, the buffer is present at a concentration of about 3 mM.

The amount and identity of the buffer may be selected in order toachieve certain performance properties for the aqueous ophthalmicsolution. For example, the amount of buffer may impact the quantity ofacid that may be neutralized before there is substantial change in thepH of the aqueous ophthalmic solution. Also, the amount of buffer mayimpact the tonicity of the aqueous ophthalmic solution. Desirably, thequantity and identity of the buffer should be selected in order tominimize any irritation that may be caused by administration of theaqueous ophthalmic solution to the eye of a patient. Accordingly, incertain embodiments, the buffer is present at a concentration in therange of about 2 mM to about 4 mM. In yet other embodiments, the bufferis present at a concentration of about 3 mM. In certain embodiments, thebuffer comprises an alkali metal alkylcarboxylate. In certain otherembodiments, the buffer comprises an alkali metal acetate. In yet otherembodiments, the buffer comprises sodium acetate.

Solution pH

The aqueous ophthalmic solution may be characterized according to the pHof the solution. Desirably, the aqueous ophthalmic solution has a pH inthe range of 4.0 to 7.5. In certain embodiments, the aqueous ophthalmicsolution has a pH in the range of 4.5 to 7.5. In certain embodiments,the solution has a pH in the range of 4.5 to 6.0. In certain otherembodiments, the solution has a pH in the range of 4.5 to 5.5. In yetother embodiments, the solution has a pH in the range of 4.7 to 5.1.

Additional Materials for Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions may contain additional materials inorder to make the composition more suitable for administration to theeye of a patient. Exemplary additional materials are described below andinclude, for example, a tonicity modifier, preservative, antioxidant,viscosity modifying agent, stabilizing agent, corneal permeationenhancing agent, and surfactants.

A. Tonicity Modifier

The aqueous ophthalmic solution may optionally comprise one or moretonicity modifiers. The tonicity modifier may be ionic or non-ionic. Incertain embodiments, the tonicity modifier may be a salt, acarbohydrate, or a polyol. Exemplary tonicity modifiers include alkalimetal or alkaline earth metal halides (such as LiBr, LiCl, LiI, KBr,KCl, KI, NaBr, NaCl, NaI, CaCl₂), and MgCl₂), boric acid, dextran (e.g.,Dextran 70), cyclodextrin, dextrose, mannitol, glycerin, urea, sorbitol,propylene glycol, or a combination thereof.

It is appreciated that the tonicity modifier may be added to the aqueousophthalmic solution in an amount sufficient to provide a desiredosmolality. In certain embodiments, the tonicity modifier is present inthe aqueous ophthalmic solution in an amount sufficient so that theaqueous ophthalmic solution has an osmolality ranging from about 50 toabout 1000 mOsm/kg, from about 100 to about 400 mOsm/kg, from about 200to about 400 mOsm/kg, or from about 280 to about 380 mOsm/kg. In certainembodiments, a tonicity modifier may be present in an amount rangingfrom about 0.01% (w/v) to about 7% (w/v), about 0.01% (w/v) to about 5%(w/v), about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1%(w/v), about 0.05% (w/v) to about 5% (w/v), about 0.05% (w/v) to about0.5% (w/v), about 1% (w/v) to about 3% (w/v), or about 2% (w/v) to about4% (w/v), of the aqueous ophthalmic solution.

B. Preservative

The aqueous ophthalmic solution may optionally comprise one or morepreservatives in order to, for example, reduce or prevent microbialcontamination. Exemplary preservatives include quaternary ammonium saltssuch as polyquaternium-1, cetrimide, benzalkonium chloride, orbenzoxonium chloride; alkyl-mercury salts of thiosalicylic acid such asthiomersal, phenylmercuric nitrate, phenylmercuric acetate, orphenylmercuric borate; parabens such as methylparaben or propylparaben;alcohols such as chlorobutanol, benzyl alcohol, phenyl ethanol,cyclohexanol, 3-pentanol, or resorcinol; a peroxide; chlorine dioxide orPURITE; guanidine derivatives such as chlorohexidine gluconate orpolyaminopropyl biguanide; and combinations thereof.

The amount of preservative can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the preservative is present in an amount less than about 5%(w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the preservative is present inan amount ranging from about 0.01% (w/v) to about 5% (w/v), about 0.01%(w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05%(w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), ofthe aqueous ophthalmic solution.

C. Antioxidant

The aqueous ophthalmic solution may optionally comprise one or moreantioxidants. Exemplary antioxidants for use in the aqueous ophthalmicsolutions described herein include water soluble antioxidants such asascorbic acid, cysteine hydrochloride, sodium bisulfate, sodiummetabisulfite, sodium bisulfite, sodium sulfite, and the like; andoil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like.

The amount of antioxidant can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the antioxidant is present in an amount less than about 5%(w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the antioxidant is present in anamount ranging from about 0.01% (w/v) to about 5% (w/v), about 0.01%(w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05%(w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), ofthe aqueous ophthalmic solution.

D. Viscosity Modifying Agent

The aqueous ophthalmic solution may optionally comprise one or moreviscosity modifying agents. The viscosity modifying agent may be used,for example, to increase the absorption of an active agent or increasethe retention time of the aqueous ophthalmic solution in the eye.Exemplary viscosity modifying agents include polyvinylpyrrolidone,methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,hydroxpropylcellulose, carboxymethylcellulose (CMC) and salts thereof(e.g., CMC sodium salt), gelatin, cellulose glycolate, sorbitol,niacinamide, an alpha-cyclodextran, polyvinyl alcohol, polyethyleneglycol, hyaluronic acid, a polysaccharide, a monosaccharide, andcombinations thereof.

The amount of viscosity modifying agent can be adjusted in order toachieve desired performance properties for the aqueous ophthalmicsolution. In certain embodiments, the viscosity modifying agent ispresent in an amount less than about 10% (w/v), 5% (w/v), 3% (w/v), 1%(w/v), or 0.1% (w/v) of the aqueous ophthalmic solution. In certainother embodiments, the viscosity modifying agent is present in an amountranging from about 0.01% (w/v) to about 5% (w/v), about 0.01% (w/v) toabout 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05% (w/v) toabout 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), of the aqueousophthalmic solution. In certain other embodiments, the viscositymodifying agent is present in an amount sufficient to provide an aqueousophthalmic solution with a viscosity in the range of about 30 centipoiseto about 100 centipoise.

The viscosity modifying agent may be a polymer that results in delayedrelease of one or more therapeutic agents in the solution. The identityof the polymer may be selected so as to achieve a desired time-releaseprofile for the one or more therapeutic agents.

E. Corneal Permeation Enhancing Agent

The aqueous ophthalmic solution may optionally comprise one or moreagents for enhancing corneal permeation of phentolamine (or apharmaceutically acceptable salt thereof). Exemplary agents forenhancing corneal permeation include polymers, organic acids, esters ofan organic acid (e.g., a monoglyceride of fatty acid having 8 to 12carbon atoms), cyclodextrin, benzalkonium chloride (BAK), EDTA, caprylicacid, citric acid, boric acid, sorbic acid, polyoxyethylene-20-stearylether (PSE), polyethoxylated castor oil (PCO), deoxycholic acid sodiumsalt (DC), cetylpyridinium chloride (CPC), laurocapram,hexamethylenelauramide, hexamethyleneoctanamide, decylmethylsulfoxide,methyl sulfone, dimethyl sulfoxide, and combinations thereof.

The amount of corneal permeation enhancing agent can be adjusted inorder to achieve desired performance properties for the aqueousophthalmic solution. In certain embodiments, the corneal permeationenhancing agent is present in an amount less than about 10% (w/v), 5%(w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmic solution. Incertain other embodiments, the corneal permeation enhancing agent ispresent in an amount ranging from about 0.01% (w/v) to about 5% (w/v),about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v),about 0.05% (w/v) to about 5% (w/v), about 0.05% (w/v) to about 0.5%(w/v), about 1% (w/v) to about 3% (w/v), or about 2% (w/v) to about 4%(w/v), of the aqueous ophthalmic solution.

F. Solubilizing Agent

The aqueous ophthalmic solution may optionally comprise one or moresolubilizing agents to improve the solubility of phentolamine (or apharmaceutically acceptable salt thereof) in the aqueous ophthalmicsolution. Exemplary solubilizing agents include, for example, a fattyacid glycerol poly-lower alkylene (i.e., a C₁ to C₇, linear or branched)glycol ester, fatty acid poly-lower alkylene glycol ester, polyalkyleneglycol (e.g., polyethylene glycol), glycerol ether of vitamin E,tocopherol polyethylene glycol 1000 succinate (TPGS), tyloxapol,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84and P-103), cyclodextrin, modified cyclodextrins, and combinationsthereof. In certain embodiments, the solubilizing agent is a modifiedcyclodextrin, such as those marketed under the brand name CAPTISOL®.

The amount of solubilizing agent can be adjusted in order to achievedesired performance properties for the aqueous ophthalmic solution. Incertain embodiments, the solubilizing agent is present in an amount lessthan about 10% (w/v), 5% (w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of theaqueous ophthalmic solution. In certain other embodiments, thesolubilizing agent is present in an amount ranging from about 0.01%(w/v) to about 5% (w/v), about 0.01% (w/v) to about 1% (w/v), about 0.1%(w/v) to about 1% (w/v), about 0.05% (w/v) to about 5% (w/v), or about0.05% (w/v) to about 0.5% (w/v), of the aqueous ophthalmic solution.

G. Stabilizing Agent

The aqueous ophthalmic solution may optionally comprise one or morestabilizing agents in order to improve the stability of the aqueousophthalmic solution to storage, etc. Stabilizing agents described in thepharmaceutical literature are contemplated to be amenable for use in theaqueous ophthalmic solutions described herein. Exemplary stabilizingagents include an alcohol (e.g., polyols, such as mannitol, glycerol,propylene glycol, sorbitol, and xylitol), polyalkylene glycols such aspolyethylene glycol, polypropylene glycol, polyethylene glycol-nonphenolether, polyethylene glycol sorbitan monolaurate, polyethylene glycolsorbitan monooleate, polyethylene glycol sorbitan monooleate,polyethylene glycol sterarate, polyethylene glycol polypropylene glycolether, polyvinyl alcohol, polyvinyl pyrrolidine, ascorbic acid, vitaminE, N-acetylcamosine (NAC), sorbic acid, and combinations thereof. Incertain embodiments, the stabilizing agent is a polymer, such as one ofthe polymers mentioned above.

The amount of stabilizing agent can be adjusted in order to achievedesired performance properties for the aqueous ophthalmic solution. Incertain embodiments, the stabilizing agent is present in an amount lessthan about 10% (w/v), 5% (w/v), or 1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the stabilizing agent is presentin an amount ranging from about 0.01% (w/v) to about 5% (w/v), about0.01% (w/v) to about 1% (w/v), or about 0.01% (w/v) to about 0.1% (w/v)of the aqueous ophthalmic solution.

H. Surfactant

The aqueous ophthalmic solution may optionally comprise one or moresurfactants. Exemplary surfactants include Polysorbate 20 (i.e.,polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (i.e.,polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (i.e.,polyoxyethylene (20) sorbitan monostearate), Polysorbate 80 (i.e.,polyoxyethylene (20) sorbitan monooleate), glyceryl stearate, isopropylstearate, polyoxyl stearate, propylene glycol stearate, sucrosestearate, polyethylene glycol, a polypropylene oxide, a polypropyleneoxide copolymer, Pluronic F68, Pluronic F-84, Pluronic P-103, an alcoholethoxylate, an alkylphenol ethoxylate, an alkyl glycoside, an alkylpolyglycoside, a fatty alcohol, hydroxypropylmethyl cellulose (HPMC),carboxymethyl cellulose (CMC), cyclodextrin, a polyacrylic acid,phosphatidyl chloline, phosphatidyl serine, and combinations thereof.

The amount of surfactant can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the surfactant is present in an amount less than about 10%(w/v), 5% (w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueousophthalmic solution. In certain other embodiments, the surfactant ispresent in an amount ranging from about 0.01% (w/v) to about 5% (w/v),about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v),about 0.05% (w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5%(w/v), of the aqueous ophthalmic solution.

I. Demulcent Polymers

The aqueous ophthalmic solution may optionally comprise one or moredemulcent polymers. Because of their ability to hold large amounts ofwater, demulcent polymers are useful for coating and moisturizing thecornea of the eye. Exemplary demulcent polymers include cellulosederivatives, dextran 40, dextran 70, gelatin, and liquid polyols.

J. Wetting Agents

The aqueous ophthalmic solution may optionally comprise one or morewetting agents. Wetting agents can be used to wet the surface of theeye. Exemplary wetting agents include polysorbates, poloxamers,tyloxapol, and lecithin.

K. Additional Materials

The aqueous ophthalmic solutions may optionally comprise one or moreadditional materials, such as acetylcysteine, cysteine, sodium hydrogensulfite, butyl-hydroxyanisole, butyl-hydroxytoluene, alpha-tocopherolacetate, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate,monothioglycerol, lauric acid sorbitol ester, triethanol amine oleate,or palmitic acid esters.

Further, the aqueous ophthalmic solutions may comprise a carrier, suchas one or more of the exemplary carriers are described in for example,Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co.,Easton, Pa. [1975]). The carrier can be, for example, a mixture of waterand a water-miscible solvent (e.g., an alcohol such as glycerin, avegetable oil, or a mineral oil). Other exemplary carriers include amixture of water and one or more of the following materials:hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, analkali metal salt of carboxymethylcellulose, hydroxymethylcellulose,methylhydroxypropylcellulose, hydroxypropylcellulose, ethyl oleate,polyvinylpyrrolidone, an acrylate polymer, a methacrylate polymer, apolyacrylamide, gelatin, an alginate, a pectin, tragacanth, karaya gum,xanthan gum, carrageenin, agar, acacia, a starch (such as starch acetateor hydroxypropyl starch), polyvinyl alcohol, polyvinyl methyl ether,polyethylene oxide, or a cross-linked polyacrylic acid.

Exemplary Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions having been generally described abovewill now be more specifically described by reference to the followingmore specific examples. The following more specific examples are onlyexemplary and are not intended to limit the scope of the invention inany way.

One such exemplary solution is an aqueous ophthalmic solution free of achelating agent comprising: (a) about 0.1% (w/v) to about 2% (w/v) ofphentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of at leastone polyol compound selected from the group consisting of is mannitol,glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of analkali metal acetate; and (d) water; wherein the solution has a pH inthe range of 4 to 6 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certainembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4 to 6.

Another such exemplary solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4.5 to 5.5 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the at least one polyol is mannitol. In certainembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.5% (w/v) to about 2% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4.5 to 5.5.

Another such exemplary solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4.5 to 5.5 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.5% (w/v) to about 1% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4.5 to 5.5.

Further exemplary aqueous ophthalmic solutions are provided in Tables1-3 below, where in each instance the solution has a pH in the range of4.7 to 5.1.

TABLE 1 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component Al B1 Cl D1 El Fl G1 H1 Phentolamine mesylate 1.5 1 0.5 1 1 11 1 (% w/v) Mannitol (% w/v) 4 4 4 3 3 2 2 4 Sodium acetate (mM) 3 3 3 33 3 3 3 Glycerol (% w/v) 0 0 0 0.5 0 1 0 0 Propylene glycol 0 0 0 0 0.50 1 0 (% w/v) Dextran 70 (% w/v) 0 0 0 0 0 0 0 0. 1 Water q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s.

TABLE 2 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A2 B2 C2 D2 E2 F2 Phentolamine mesylate 0.25 0.25 0.25 0.250.25 0.25 (% w/v) Mannitol (% w/v) 4 3 3 2 2 4 Sodium acetate (mM) 3 3 33 3 3 Glycerol (% w/v) 0 0.5 0 1 0 0 Propylene glycol 0 0 0.5 0 1 0 (%w/v) Dextran 70 (% w/v) 0 0 0 0 0 0.1 Water q.s. q.s. q.s. q.s. q.s.q.s.

TABLE 3 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A3 B3 C3 D3 E3 F3 G3 H3 Phentolamine mesylate 1.5 1 0.5 0.25 11 1 1 (% w/v) Mannitol (% w/y) 4 4 4 4 3 2 2 4 Sodium acetate (mM) 3 3 33 3 3 2 3 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Another exemplary aqueous ophthalmic solution comprises phentolaminemesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v), dextran having aweight average molecular weight of about 70,000 g/mol (e.g., at 0.1%w/v), hydroxypropyl methylcellulose (e.g., at 0.3% w/v), potassiumchloride, purified water, sodium borate, and sodium chloride; whereinthe solution has a pH in the range of about 4 to about 6. In certainembodiments, the solution has a pH in the range of 4.5 to 5.1. Incertain embodiments, the aqueous ophthalmic solution consistsessentially of phentolamine mesylate (e.g., at 1% w/v), mannitol (e.g.,at 4% w/v), dextran having a weight average molecular weight of about70,000 g/mol (e.g., at 0.1% w/v), hydroxypropyl methylcellulose (e.g.,at 0.3% w/v), potassium chloride, purified water, sodium borate, andsodium chloride; wherein the solution has a pH in the range of 4 to 6.In certain other embodiments, the aqueous ophthalmic solution consistsof phentolamine mesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v),dextran having a weight average molecular weight of about 70,000 g/mol(e.g., at 0.1% w/v), hydroxypropyl methylcellulose (e.g., at 0.3% w/v),potassium chloride, purified water, sodium borate, and sodium chloride;wherein the solution has a pH in the range of 4.5 to 5.1.

Another exemplary aqueous ophthalmic solution comprises phentolaminemesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v), sodium acetate(e.g., at 3 mM), and water, wherein the solution has a pH in the rangeof about 4 to about 6. In certain embodiments, the solution has a pH inthe range of 4.5 to 5.1. In certain embodiments, the aqueous ophthalmicsolution consists essentially of phentolamine mesylate (e.g., at 1%w/v), mannitol (e.g., at 4% w/v), sodium acetate (e.g., at 3 mM), andwater, wherein the solution has a pH in the range of 4 to 6. In certainembodiments, the aqueous ophthalmic solution comprises phentolaminemesylate at 1% w/v, mannitol 4% w/v, sodium acetate at 3 mM, and water,wherein the solution has a pH in the range of 4.5 to 5.1. In certainother embodiments, the aqueous ophthalmic solution consists ofphentolamine mesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v),sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pHin the range of 4.5 to 5.1. In certain embodiments, the aqueousophthalmic solution consists essentially of phentolamine mesylate at 1%w/v, mannitol 4% w/v, sodium acetate at 3 mM, and water, wherein thesolution has a pH in the range of 4.5 to 5.1.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.1% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4 to 6 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.25% (w/v) to about 2%(w/v) of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.1% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent. In certain embodiments, the aqueousophthalmic solution free of a chelating agent that comprises about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.5 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 1% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 1 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.1% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent. In certainembodiments, the aqueous ophthalmic solution free of a chelating agentthat comprises about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.5% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of a buffer comprising sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.5 to 5.2 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of a buffer comprising sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 1% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 1 mM to about 4 mM of a buffer comprising sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.1% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM of a buffercomprising sodium acetate; and (d) water; wherein the solution has a pHin the range of 4.6 to 5.2 and does not contain a chelating agent. Incertain embodiments, the aqueous ophthalmic solution free of a chelatingagent that comprises about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.5% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM of a buffercomprising sodium acetate; and (d) water; wherein the solution has a pHin the range of 4.6 to 5.2 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of a buffer comprising sodiumacetate; (d) water; and (e) pilocarpine (e.g., from about 0.1% w/w toabout 1% w/w pilocarpine); wherein the solution has a pH in the range of4.5 to 6.0 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of a buffer comprising sodiumacetate; (d) water; and (e) pilocarpine (e.g., from about 0.1% w/w toabout 1% w/w pilocarpine); wherein the solution has a pH in the range of4.6 to 6.0 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 1% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 1 mM to about 4 mM of a buffer comprising sodiumacetate; (d) water; and (e) pilocarpine (e.g., from about 0.1% w/w toabout 1% w/w pilocarpine); wherein the solution has a pH in the range of4.6 to 6.0 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.1% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM of a buffercomprising sodium acetate; (d) water; and (e) pilocarpine (e.g., fromabout 0.1% w/w to about 1% w/w pilocarpine); wherein the solution has apH in the range of 4.6 to 6.0 and does not contain a chelating agent. Incertain embodiments, the aqueous ophthalmic solution free of a chelatingagent that comprises about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.5% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM of a buffercomprising sodium acetate; (d) water; and (e) pilocarpine (e.g., fromabout 0.1% w/w to about 1% w/w pilocarpine); wherein the solution has apH in the range of 4.6 to 6.0 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution,comprising: (a) about 0.25% (w/v) to about 2% (w/v) of phentolaminemesylate; (b) about 3% (w/v) to about 5% (w/v) of mannitol; (c) about 2mM to about 4 mM of a buffer comprising sodium acetate; (d) water; and(e) pilocarpine (e.g., from about 0.1% w/w to about 1% w/w pilocarpine);wherein the solution has a pH in the range of 4.5 to 6.0.

Yet another exemplary solution is an aqueous ophthalmic solution,comprising: (a) about 0.5% (w/v) to about 2% (w/v) of phentolaminemesylate; (b) about 3% (w/v) to about 5% (w/v) of mannitol; (c) about 2mM to about 4 mM of a buffer comprising sodium acetate; (d) water; and(e) pilocarpine (e.g., from about 0.1% w/w to about 1% w/w pilocarpine);wherein the solution has a pH in the range of 4.6 to 6.0.

Yet another exemplary solution is an aqueous ophthalmic solution,comprising: (a) about 0.5% (w/v) to about 1% (w/v) of phentolaminemesylate; (b) about 3% (w/v) to about 5% (w/v) of mannitol; (c) about 1mM to about 4 mM of a buffer comprising sodium acetate; (d) water; (e)pilocarpine (e.g., from about 0.1% w/w to about 1% w/w pilocarpine); and(f) glycerol; wherein the solution has a pH in the range of 4.6 to 6.0.

Yet another exemplary solution is an aqueous ophthalmic solution,comprising: (a) about 0.1% (w/v) to about 1% (w/v) of phentolaminemesylate; (b) about 4% mannitol; (c) about 3 mM of a buffer comprisingsodium acetate; (d) water; (e) pilocarpine (e.g., from about 0.1% w/w toabout 1% w/w pilocarpine); and (f) glycerol; wherein the solution has apH in the range of 4.6 to 6.0. In certain embodiments, the aqueousophthalmic solution free of a chelating agent that comprises about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate.

Yet another exemplary solution is an aqueous ophthalmic solution,comprising: (a) about 0.5% (w/v) to about 1% (w/v) of phentolaminemesylate; (b) about 4% mannitol; (c) about 3 mM of a buffer comprisingsodium acetate; (d) water; (e) pilocarpine (e.g., from about 0.1% w/w toabout 1% w/w pilocarpine); and (f) glycerol; wherein the solution has apH in the range of 4.6 to 6.0.

Stability Features of Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions described herein may be furthercharacterized according to their stability features, such as thepercentage of phentolamine (or pharmaceutically acceptable salt thereof)that is present in the aqueous ophthalmic solution after storage for acertain length of time. As explained above, one of the benefits of thepresent aqueous ophthalmic solutions is that they possess good stabilityover extended periods of time, even though they do not have a chelatingagent.

Accordingly, in certain embodiments, the aqueous ophthalmic solution ischaracterized by less than 2% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage of thesolution at 25° C. for 12 weeks. In certain other embodiments, theaqueous ophthalmic solution is characterized by less than 2% by weightof the phentolamine or pharmaceutically acceptable salt thereof degradesupon storage at 25° C. for 24 weeks (or 36 weeks or 48 weeks). In yetother embodiments, less than 7% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage at 40° C.for 12 weeks (or 24, 36, or 48 weeks). In yet other embodiments, theaqueous ophthalmic solution is characterized by less than 10% by weightof the phentolamine or pharmaceutically acceptable salt thereof degradesupon storage at 25° C. for 18 months, 24 months, or 36 months. In yetother embodiments, the aqueous ophthalmic solution is characterized byless than 10% by weight of the phentolamine or pharmaceuticallyacceptable salt thereof degrades upon storage at temperature in therange of 2-8° C. for 18 months, 24 months, or 36 months. In yet otherembodiments, the aqueous ophthalmic solution is characterized by lessthan 4% by weight (or preferably less than 3% by weight) of thephentolamine or pharmaceutically acceptable salt thereof degrades uponstorage at 25° C. for 18 months, 24 months, or 36 months. In yet otherembodiments, less than 10% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage at 40° C.for 4, 5, or 6 months.

Polyvinylpyrrolidone Artificial Tears Formulation

Another ophthalmic solution contemplated for use in the presentinvention is an ophthalmic solution comprising a therapeutic agent(e.g., an alpha-adrenergic antagonist, such as phentolamine or apharmaceutically acceptable salt thereof) and a polyvinylpyrrolidoneartificial tears composition. Exemplary polyvinylpyrrolidone artificialtears compositions are described in, for example, U.S. Pat. Nos.5,895,654; 5,627,611; and 5,591,426; and U.S. Patent ApplicationPublication No. 2002/0082288, all of which are hereby incorporated byreference. Artificial tears compositions are understood to promotewettability and spread, have good retention and stability on the eye,and desirably do not cause any significant discomfort to the user.Accordingly, an exemplary polyvinylpyrrolidone artificial tearcomposition comprises: (1) polyvinylpyrrolidone, preferably in theamount of about 0.1-5% by weight of the solution; (2) benzalkoniumchloride, preferably in an amount of about 0.01-0.10% by weight of thesolution; (3) hydroxypropyl methylcellulose, preferably in an amount ofabout 0.2-1.5% by weight of the solution; (4) glycerin, preferably in anamount of about 0.2-1.0% by weight of the solution, and (5) water,wherein the composition is an aqueous solution having isotonicproperties.

Sustained Release Delivery Systems

When it is desirable to have sustained release of one or moretherapeutic agents to the patient, the therapeutic agent(s) may beadministered to the patient in the form of a sustained release deliverysystem. Sustained release delivery systems are described in thepublished literature. Exemplary sustained release delivery systemsinclude intracanalicular inserts, a slow release contact lens, abio-erodible IVT insert, and an intracameral insert. Inserts may bebiodegradable or non-biodegradable. Exemplary materials described in theliterature for use in sustained release delivery systems include amixture of EVA and PVA polymers, a mixture of silicone and PVA polymer,a mixture of polyimide and PVA polymer, a mixture of PMMA and EVApolymers, PLGA polymer, and liposomes. In certain embodiments, anophthalmic solution may contain an oil, such as an oil with viscosityhigh enough to impede removal of the active ingredient from the surfaceof the eye when an aliquot of the ophthalmic solution is applied to thesurface of the eye.

IV. Medical Kits

Another aspect of the invention provides a medical kit comprising, forexample, (i) a therapeutic agent described herein, and (ii) instructionsfor treating presbyopia, mydriasis, and/or other ocular disordersaccording to methods described herein.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustrating certain aspects and embodiments ofthe present invention, and are not intended to limit the invention.

Example 1—Treatment of Presbyopia by Phentolamine Mesylate in HumanSubjects

Ability of phentolamine mesylate to treat a human subject suffering frompresbyopia may be evaluated according to a clinical study in which anaqueous ophthalmic solution containing phentolamine mesylate isadministered to the eye of a patient, and then the patient is evaluatedfor improvement in visual performance, including near-visual visualperformance. Experimental procedures and results are described below

Part I—Experimental Procedures

Human subjects are screened for potential enrollment and, if qualified,enrolled in the study. Exemplary inclusion criteria and exclusioncriteria for the study are set forth below. If a subject does not meetthe inclusion/exclusion criteria but the investigator believes thesubject should be in the study, a deviation may be allowed following adiscussion between the Principal Investigator and Sponsor of the study.

Inclusion Criteria

-   -   45 to 55 years of age.    -   Distance Corrected Near Visual Acuity worse than 20/40.    -   Best Corrected Distance Visual Acuity of 20/20 or better in each        eye.    -   Able and willing to give informed consent and comply with all        protocol mandated procedures.

Exclusion Criteria

-   -   Certain pupillary conditions.    -   Significant astigmatism, glaucoma, diabetes, cataracts, eye        surgery, ocular trauma or accommodative issues.    -   Contact lens wear within 3 days prior to and for duration of        study.    -   Use of a prohibited medication.    -   Participation in any investigational study within the past 30        days.

Human subjects enrolled in the study shall randomized into two (or more)Treatment Groups with a 1:1 randomization. The Treatment Groups willreceive single doses of either:

-   -   Placebo Ophthalmic Solution,    -   1% w/w Phentolamine Mesylate Ophthalmic Solution, or    -   2% w/w Phentolamine Mesylate Ophthalmic Solution.        Description of the study medications is provided in Table 1.

TABLE 1 Study Medication Study Medication Composition of StudyMedication Placebo Ophthalmic 4% w/w mannitol Solution 3 mM sodiumacetate water pH in the range 4.8 to 5.0 1% w/w Phentolamine 1% w/wphentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3 mMsodium acetate water pH in the range 4.8 to 5.0 2% w/w Phentolamine 2%w/w phentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3mM sodium acetate water pH in the range 4.8 to 5.0

Doses of study medication are given once daily for one or more weeks.Visual performance will be evaluated, which may include analysis ofnear-vision visual acuity, Best Corrected Distance Visual Acuity(BCDVA), Distance Corrected Near Vision Acuity (DCNVA), and/or Visionquestionnaire.

Example 2—Treatment of Presbyopia by Phentolamine Mesylate in HumanSubjects

Ability of phentolamine mesylate to treat a human subject suffering frompresbyopia may be evaluated according to a clinical study in which anaqueous ophthalmic solution containing phentolamine mesylate isadministered to the eye of a patient, and then the patient is evaluatedfor improvement in visual performance, including near-visual visualperformance. Experimental procedures and results are described below.

Part I—Experimental Procedures

Human subjects are screened for potential enrollment and, if qualified,enrolled in the study. Exemplary inclusion criteria and exclusioncriteria for the study are set forth below. If a subject does not meetthe inclusion/exclusion criteria but the investigator believes thesubject should be in the study, a deviation may be allowed following adiscussion between the Principal Investigator and Sponsor of the study.

Inclusion Criteria

-   -   Be able and willing to provide written informed consent and sign        Health Information Portability and Accountability Act (HIPAA)        form prior to any study procedure being performed.    -   Be able and willing to follow all instructions and attend study        visits.    -   Be 48-64 years of age of either sex and any race or ethnicity at        visit 1.    -   Be an early to moderate presbyope determined by screening        monocular best-corrected distance visual acuity (VA) at 45 cm.    -   Be able and willing to avoid all disallowed medications for the        appropriate washout period and during the study without        significant risk to the subject.

Exclusion Criteria

-   -   Be a female of childbearing potential who is currently pregnant,        nursing or planning a pregnancy.    -   Have known contraindications or sensitivity to the use of any of        the study medications(s) or their components.    -   Have an active ocular infection at visit 1 (bacterial, viral or        fungal), positive history of an ocular herpetic infection,        preauricular lymphadenopathy, or ongoing, active ocular        inflammation (e.g., moderate to severe blepharitis, allergic        conjunctivitis, peripheral ulcerative keratitis, scleritis,        uveitis) in either eye.    -   Have moderate or severe dry eye.    -   Have clinically significant abnormal lens findings (e.g.,        cataract) including early lens changes and/or any evidence of a        media opacity in either eye.    -   Have dark-adapted pupillometry measurements of <4.0 mm in either        eye.    -   Have intraocular pressure (IOP) that is less than 5 millimeters        of mercury (mmHg) or greater than 22 mmHg in either eye        documented at visit 1, or have a prior diagnosis of ocular        hypertension or glaucoma or currently being treated with any        type of topical IOP lowering (glaucoma) medication at visit 1.    -   Have abnormal findings on dilated fundus exam in either eye        documented within 3 months of visit 1 or a known history of        retinal detachment or clinically significant retinal disease in        either eye.    -   Have a known history or diagnosis in the past of: iritis,        scleritis or uveitis, whether active or inactive.    -   Have had surgical intervention (ocular or systemic) within 6        months prior to visit 1, or planned surgical intervention within        30 days after visit 4.    -   Have undergone refractive eye surgery (incisional keratotomy,        photorefractive keratectomy [PRK], laser in situ keratomileusis        [LASIK], laser-assisted sub-epithelial keratectomy [LASEK]),        corneal inlay procedures, cataract extraction, or intraocular        lens placement.    -   Use artificial tears or lubricant eye ointment on a daily basis.    -   Have an inability or refuse to discontinue soft contact lens        wear 7 days prior to study visit 1 and rigid gas permeable (RGP)        contact lens wear 14 days prior to visit 1 and during the study.    -   Use any of the following disallowed medications during the 2        weeks (14 days) prior to visit 1 and during the study: (1)        narcotic (opiate class) pain medication (e.g., codeine,        OxyContin®, Vicodin®, Tramadol®); (2) bladder medication (e.g.,        Urecholine®, bethanechol); (3) antipsychotics; (4)        antidepressants; (5) attention-deficit/hyperactivity disorder        (ADHD) medications; (6) alpha-blockers (e.g., tamsulosin,        Flomax®, Jayln®, Uroxatral®, Rapaflo®); (7) anticholinergics        (e.g., atropine, belladonna, benztropine, dicyclomine,        donepezil, hyoscyamine, propantheline, scopolamine,        trihexphenidyl); (8) muscarinic receptor agonists or cholinergic        agonists (e.g., Salagen®, Evoxac®); (9) over-the-counter (OTC)        or prescription antihistamines or decongestants; (10) any        prescribed topical ophthalmic medications; or (11) recreational        drug use (e.g., marijuana, methadone, heroin, cocaine).    -   Have a diagnosis of diabetes mellitus or a history of elevated        blood sugar.    -   Have a condition or a situation, which in the Investigator's        opinion, may put the subject at increased risk, confound study        data, or interfere significantly with the subject's study        participation, including but not limited to unstable:        cardiovascular, hepatic, renal, respiratory, gastrointestinal,        endocrine, immunologic, dermatologic, hematologic, neurologic,        or psychiatric disease.

Human subjects enrolled in the study shall randomized into two (or more)Treatment Groups with a 1:1 randomization. The Treatment Groups willreceive single doses of either:

-   -   Placebo Ophthalmic Solution,    -   1% w/w Phentolamine Mesylate Ophthalmic Solution, or    -   2% w/w Phentolamine Mesylate Ophthalmic Solution.        Description of the study medications is provided in Table 1.

TABLE 1 Study Medication Study Medication Composition of StudyMedication Placebo Ophthalmic 4% w/w mannitol Solution 3 mM sodiumacetate water pH in the range 4.8 to 5.0 1% w/w Phentolamine 1% w/wphentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3 mMsodium acetate water pH in the range 4.8 to 5.0 2% w/w Phentolamine 2%w/w phentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3mM sodium acetate water pH in the range 4.8 to 5.0

Doses of study medication are given once daily for one or more weeks.Visual performance will be evaluated, which may include analysis ofnear-vision visual acuity, Best Corrected Distance Visual Acuity(BCDVA), Distance Corrected Near Vision Acuity (DCNVA), and/or Visionquestionnaire.

One measure of performance is the proportion of subjects with at least a3 line (15 letter) improvement in the study eye in the measurement ofpost-treatment monocular best-corrected distance visual acuity at 45 cmcompared to baseline monocular best-corrected distance visual acuity at45 cm up to 7 hours post-treatment.

Another measure of performance is the proportion of subjects with atleast a 3 line (15 letter) improvement in the study eye in themeasurement of post-treatment near vision acuity compared to baseline,such as at up to 7 hours post-treatment.

Example 3—Reversal of Mydriasis in Human Subjects Using PhentolamineMesylate

Ability of phentolamine mesylate to reverse pharmacologically inducedmydriasis in the eye of normal, healthy human subjects was evaluatedaccording to a randomized, cross-over, double-masked, placebo-controlledclinical study. Approximately 32 subjects were enrolled and randomized1:1 into one of two treatment sequences. All subjects were firstadministered a mydriatic agent (phenylephrine (2.5% w/w) or tropicamide(1% w/w)) by delivery of an eye drop containing the mydriatic agent tothe subject's eyes. Then, approximately one hour after receiving themydriatic agent, the subject was administered study medication accordingto Treatment Protocol 1 or Treatment Protocol 2.

In Treatment Protocol 1, the subject received placebo on the firsttreatment day (Visit 1/Day 1) and received 1% w/w Phentolamine MesylateOphthalmic Solution on the second treatment day (Visit 2/Day 8+2 days).In Treatment Protocol 2, the subject received 1% w/w PhentolamineMesylate Ophthalmic Solution on the first treatment day (Visit 1/Day 1)and received placebo on the second treatment day (Visit 2/Day 8+2 days).The study eye was defined as the eye with the larger pupil diameter atmaximum (1 hour after instillation of the mydriatic agent) at Visit 1.If both eyes had the same pupil diameter at maximum, then the study eyewas the right eye. This was the study eye for both Visit 1 and Visit 2assessments.

All treatments were administered to both eyes in the subject. At eachvisit, pupil diameter, accommodation, near and distance visual acuity(VA) and redness in each eye was measured before (−1 hour/baseline) and1 hour after (0 minutes/maximum) the mydriatic agent instillation ineach eye (i.e., right before the study treatment was administered), andat 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after treatmentdosing. Efficacy and safety were evaluated, which included analysis ofreduction in pupil diameter. Further aspects of the experimentalprocedures and results are described below.

Part I—Experimental Procedures

Human subjects were screened for potential enrollment and, if qualified,enrolled in the study. Inclusion criteria and exclusion criteria for thestudy are set forth below. Subjects enrolled in the study wererandomized in a 1:1 ratio to one of two treatment sequences (the firsttreatment sequence entailed subjects receiving placebo on the firsttreatment day and receiving 1% w/w Phentolamine Mesylate OphthalmicSolution on the second treatment day; the second treatment sequenceentailed subjects receiving 1% w/w Phentolamine Mesylate OphthalmicSolution on the first treatment day and receiving placebo on the secondtreatment day). Randomization was stratified by mydriatic agent(phenylephrine or tropicamide), with randomization into each stratumcapped at approximately 16 subjects (approximately half of therandomized subjects received phenylephrine, half received tropicamide).Subjects received their mydriatic agent 1 hour before treatment.Treatment Visit 1 was on Day 1, when the subject received the firsttreatment in his/her treatment sequence. Treatment Visit 2 was on Day8+2 days, when the subject received the second treatment in his/hertreatment sequence. Each subject received the same mydriatic agentthroughout the study. Efficacy and safety were evaluated as describedbelow. Study medication is listed in Table 1.

TABLE 1 Study Medication Study Medication Composition of StudyMedication 1% w/w Phentolamine 1% w/w phentolamine mesylate MesylateOphthalmic 4% w/w mannitol Solution 3 mM buffer comprising sodiumacetate and acetic acid water pH in the range 4.8 to 5.0 Placebo 4% w/wmannitol 3 mM buffer comprising sodium acetate and acetic acid water pHin the range 4.8 to 5.0

Inclusion Criteria

-   -   1. Males or females ≥18 and ≤45 years of age with brown irides        only.    -   2. Otherwise healthy and well-controlled subjects.    -   3. Ability to comply with all protocol mandated procedures and        to attend all scheduled office visits.    -   4. Willing to give written informed consent to participate in        this study.

Exclusion Criteria

-   -   1. Clinically significant ocular disease as deemed by the        Investigator (e.g., cataract, glaucoma, corneal edema, uveitis,        severe keratoconjunctivitis sicca) that might interfere with the        study.    -   2. Unwilling or unable to discontinue use of contact lenses        during treatment visits.    -   3. Ocular trauma, ocular surgery or non-refractive laser        treatment within the 6 months prior to screening.    -   4. Ocular medication of any kind within 30 days of screening,        with the exception of a) lid scrubs (which may have been used        prior to, but not after screening) or b) lubricating drops for        dry eye (preservative-free artificial tears), which were allowed        to be used in between the study treatment days.    -   5. Recent or current evidence at Screening of ocular infection        or inflammation. Current evidence of clinically significant        blepharitis, conjunctivitis, or a history of herpes simplex or        herpes zoster keratitis at Screening.    -   6. History of diabetic retinopathy.    -   7. Closed or very narrow angles that in the Investigator's        opinion were potentially occludable if the subject's pupil was        dilated.    -   8. History of any traumatic (surgical or nonsurgical) or        non-traumatic condition affecting the pupil or iris (e.g.,        irregularly-shaped pupil, neurogenic pupil disorder, iris        atrophy, iridotomy).    -   9. Known allergy or contraindication to any component of the        mydriatic agents or the vehicle formulation.    -   10. Known hypersensitivity or contra-indication to α- and/or        β-adrenoceptor antagonists (e.g. chronic obstructive pulmonary        disease or bronchial asthma; abnormally low blood pressure (BP)        or heart rate (HR); second or third-degree heart block or        congestive heart failure (CHF); severe diabetes).    -   11. Clinically significant systemic disease (e.g., uncontrolled        diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine        or cardiovascular disorders) that might have interfered with the        study.    -   12. Initiation of treatment with, or any changes to the current        dosage, drug or regimen of any topical or systemic adrenergic or        cholinergic drugs up to 7 days prior to Screening, or during the        study.    -   13. Participation in any investigational study within 30 days        prior to screening.    -   14. Women of childbearing potential who were pregnant, nursing,        planning a pregnancy, or not using a medically acceptable form        of birth control. Acceptable methods include the use of at least        one of the following: intrauterine device (IUD), hormonal (oral,        injection, patch, implant, ring), barrier with spermicide        (condom, diaphragm), or abstinence. An adult woman was        considered to be of childbearing potential unless she was 1 year        postmenopausal or 3 months post-surgical sterilization. All        females of childbearing potential must have had a negative urine        pregnancy test result at Visit 1 Screening and Visit 2        examinations and must have intended to not become pregnant        during the study.    -   15. Resting HR outside the normal range (50-110 beats per        minute) at the Screening Visit. HR was allowed to be repeated        only once if outside the normal range following at least a        5-minute rest period in the sitting position.    -   16. Hypertension with resting diastolic BP>105 mmHg or systolic        BP>160 mmHg at the Screening Visit. BP was allowed to be        repeated only once if outside the specified range following at        least a 5-minute rest period in the sitting position.

As noted in the exclusion criteria, the following were prohibited duringthe study:

-   -   Use of ocular medication within 30 days of the Screening Visit,        or anticipated use during the study, with the exception of        lubricating drops for dry eye (preservative-free artificial        tears), which were allowed to be used throughout the study.    -   Initiation of treatment with, or any changes to the dosage,        drug, or regimen of any topical or systemic adrenergic or        cholinergic drugs up to 7 days prior to Screening, or during the        study. A large number of drugs, both prescription and        over-the-counter (OTC), contain active ingredients that can        affect pupil diameter. This includes many eye drops, such as        Visine, that would be used to reduce redness, most cough or cold        preparations, antihistamines and bronchodilators, most        nose-drops, most blood-pressure medications, many drugs used for        migraines, and many other products.

Intermittent use of OTC lubricating drops for dry eye (preservative freeartificial tears) was acceptable between treatment visits. However, noother ocular medications (OTC or prescription) were allowed within 30days of the Screening Visit, or during the study.

Analysis of Efficacy

The primary efficacy endpoint was the change in pharmacologicallyinduced mydriatic (max) pupil diameter (0 minutes) at 2 hourspost-treatment in the study eye. The study eye was defined as the eyewith the larger pupil diameter at maximum (1 hour after instillation ofthe mydriatic agent) at Visit 1. If both eyes had the same pupildiameter at maximum, then the study eye was the right eye. This was thestudy eye for both Visit 1 and Visit 2 assessments.

Secondary efficacy endpoints (for the study eye; for the non-study eye;and for both eyes) included:

-   -   Change (in mm) from max pupil diameter (0 minutes) at each        remaining timepoint (30 min, 1 hour, 4 hours, 6 hours).    -   Percentage of subjects who achieved a pre-specified reduction of        ≥2 mm, ≥3 mm, and ≥4 mm from max pupil diameter at each        timepoint (30 min, 1 hour, 2 hours, 4 hours, 6 hours).    -   Percentage of subjects who achieved pupil diameter of no more        than 0.5 mm above baseline (−1 hour) at each timepoint (0 min,        30 min, 1 hour, 2 hours, 4 hours, 6 hours).    -   Change from baseline (−1 hour) in accommodation at each        timepoint (0 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours).    -   Percent of subjects with unchanged accommodation from baseline        (−1 hour) at each timepoint (0 min, 30 min, 1 hour, 2 hours, 4        hours, 6 hours).    -   Change from baseline (−1 hour) in BCDVA at each timepoint (0        min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours).    -   Percent of subjects who returned to baseline (−1 hour) BCDVA at        each timepoint (0 min, 30 min, 1 hour, 2 hours, 4 hours, 6        hours).    -   Change from baseline (−1 hour) in DCNVA at each timepoint (0        min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours).    -   Percent of subjects who returned to baseline (−1 hour) DCNVA at        each timepoint (0 min, 30 min, 1 hour, 2 hours, 4 hours, 6        hours).    -   Change from baseline (−1 hour) in conjunctival hyperemia at each        timepoint (30 min, 1 hour, 2 hours, 4 hours, 6 hours), for study        eye and non-study eye; in all subjects, in subjects taking        LUMIFY® (which is an ophthalmic solution containing brimonidine        tartrate (0.025% w/w) marketed by Bausch & Lomb, Inc.), and in        subjects not taking LUMIFY®.

Each efficacy endpoint was analyzed overall and by mydriatic agent.

Assessing, Recording, and Analyzing of Efficacy Parameters

Pupil diameter, accommodation, near and distance visual acuity wasmeasured at the Screening Visit (which was also the same day asTreatment Visit 1) and Treatment Visit 2.

-   -   Pupil diameter was measured with the Neuroptics pupillometer        (mm).    -   Accommodation was measured by the Near Point Rule (Diopters).        Worsening of accommodation was defined as an amplitude decrease        of greater than 1 diopter compared to baseline. Unchanged also        included improvernent in accommodation.    -   DCNVA Reading/Near was measured by standard reading card        (Original Series Sloan Letter Early Treatment Diabetic        Retinopathy Study (ETDRS) card, LogMAR units).    -   BCDVA Distance was measured by Standard ETDRS chart (Letters).    -   Redness was assessed visually with the CCLRU bulbar redness        scale (0-3).

All assessments were conducted under photopic conditions. The photopiclighting conditions were to be kept the same during the 2 treatmentvisits. Every effort was made to have the same person perform themeasurements at all timepoints and at all visits.

Screening/Day 1

Individuals who were potential subjects were contacted by the studycenter to schedule the Screening visit. This visit occurred the same dayas Treatment Visit 1, when the first dose of study treatment was given.

Once subjects arrived at the study center, a member of the study centerstaff interviewed the individual as to their qualifications forparticipation in the study, and if the subject wished to continue, theInformed Consent form was signed, and a Screening number was assigned.Screening included an explanation of the study, a medical and ophthalmichistory, HR and BP, and a review of prior/concomitant medications. Thesecond step in screening included procedures such as a urine pregnancytest (for females of childbearing potential), IOP assessment and anophthalmic examination that included biomicroscopy and direct orindirect ophthalmoscopy without dilation.

Treatment Visit 1/Day 1

Treatment Visit 1 was the same day as Screening. Once the subjectcompleted the Screening assessments part of the visit and it wasconfirmed that he/she met all of the inclusion criteria but none of theexclusion criteria, the visit then transitioned to the Treatment Visit 1assessments. As part of the Treatment Visit 1, the subject:

-   -   Was randomized to one of two treatment sequences, with        randomization stratified by mydriatic agent.    -   Received one of two approved mydriatic agents (1% w/w        tropicamide or 2.5% w/w phenylephrine) at −1 hour/baseline. The        mydriatic agent was administered as a single drop to each eye.        If the drop was missed, the Investigator was to give the drop        again.    -   Received the first of the two study treatments, based on his/her        randomized treatment sequence at 0±5 minutes/maximum.    -   Was assessed for ocular tolerability at 0+5 minutes/maximum        following instillation of study medication.    -   Was assessed at −1 hour/baseline, 0+5 minutes/maximum, 30+5        minutes, 1 hour+5 mins, 2 hours+10 mins, 4 hours+15 mins and 6        hours+15 mins relative to study treatment for the following:        pupil diameter; BCDVA; DCNVA; accommodation; and conjunctival        redness as well as any adverse event (AE).    -   Had an IOP assessment at 6 hours+15 mins.    -   Was assessed at screening, −1 hour/baseline, 2 hours+10 mins,        and 6 hours+15 mins relative to study treatment for HR and BP.

The study eye was defined as the eye with the larger pupil diameter atmaximum (1 hour after instillation of the mydriatic agent) at Visit 1.If both eyes had the same pupil diameter at maximum, then the study eyewas the right eye. This was the study eye for both Visit 1 and Visit 2assessments.

As needed, two hours post treatment, subjects were allowed to requestthe administration of LUMIFY® (which is an ophthalmic solutioncontaining brimonidine tartrate (0.025% w/w) marketed by Bausch & Lomb,Inc.) in the non-study eye (and the site was to record such usage).

Treatment Visit 2/Day 8+2 Days

On Study Day 8+2 Days, the subject returned to the clinic for TreatmentVisit 2. As part of the Treatment Visit 2, the subject:

-   -   Underwent a review of concomitant medications and females of        childbearing potential received a urine pregnancy test.    -   Received the same approved mydriatic agent that he/she received        at Treatment Visit 1 (1% tropicamide or 2.5% phenylephrine) at        −1 hour/baseline. The mydriatic agent was administered as a        single drop to each eye. If the drop was missed, the        Investigator was to give the drop again.    -   Received the second of the two study treatments based on his/her        randomized treatment sequence at 0+5 minutes/maximum.    -   Was assessed for ocular tolerability at 0+5 minutes/maximum        following instillation of study medication.    -   Was assessed at—1 hour/baseline, 0+5 mins minutes/maximum, 30        minutes+5 mins, 1 hour±5 mins, 2 hours+10 mins, 4 hours+15 mins        and 6 hours+15 mins relative to study treatment for the        following: pupil diameter; BDCVA; DCNVA; accommodation; and        conjunctival redness as well as any AEs.    -   Had an IOP assessment at 6 hours+15 mins.    -   Was assessed at −1 hour/baseline, 2 hours+10 mins and 6 hours+15        mins relative to study treatment for HR and BP.

As needed, two hours post treatment, subjects were allowed to requestthe administration of LUMIFY® (which is an ophthalmic solutioncontaining brimonidine tartrate (0.025% w/w) marketed by Bausch & Lomb,Inc.) in the non-study eye and such usage would be recorded.

Unscheduled Visits

An Unscheduled Visit was any visit to the Investigator other than thespecific visits requested in the protocol, as possibly required for thesubject's ophthalmic condition. The Investigator was to perform allprocedures necessary to evaluate the study participant at these visitsand record any AEs in the case report form (CRF).

Visit Variation

Visits on Day 8 may be up to 2 days late.

Efficacy Determination

Efficacy was assessed using the full analysis set (FAS) with subjectsincluded in the treatment sequence in which they were randomized,regardless of the treatment sequence they actually received. For theanalysis of the primary efficacy endpoint, observed case data was used(no imputation was performed for missing data) for the primary analysis.Confirmatory analyses could have been performed using the all randomizedpopulation (ARP), with imputation performed for missing data. For theanalysis of the secondary efficacy endpoints, only observed case datawas used. If warranted, confirmatory analyses using the ARP withimputation for missing data was also performed for the secondaryefficacy endpoints.

For all efficacy endpoints, Baseline for a specific day (Visit 1, Visit2) was defined as −1 hour prior to treatment. Max timepoint was definedas time 0 minutes, during which maximum pupil diameter was expected.

All efficacy data was summarized by treatment group, study day, andtimepoint (−1 hour, 0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6hours; at Visit 1 and at Visit 2), as appropriate.

The primary efficacy endpoint was the change in pharmacologicallyinduced mydriatic (max) pupil diameter (0 minutes) at 2 hourspost-treatment in the study eye. The primary efficacy endpoint wasanalyzed using analysis of covariance (ANCOVA) with change from maxpupil diameter (0 minutes) to 2 hours in mean pupil diameter (mm) as thedependent variable; treatment sequence, subject within treatmentsequence, period, treatment and mydriatic agent as factors; and maxpupil diameter (0 minutes) as the covariate. The ANCOVA was performedusing the FAS, with subjects included in their randomized treatmentsequence regardless of the treatment they actually received. Observedcase data only was used; that is, missing values were not imputed. Theleast-squares mean (LSM) and standard error (SE) were provided for bothtreatment groups, along with the placebo-corrected LSM, its 95%confidence interval (CI) and associated p-value. A confirmatory analysisof the primary efficacy endpoint may have been performed, using the ARPwith missing values imputed. In addition, the primary efficacy endpointwas analyzed by mydriatic agent using the same model as above butwithout mydriatic agent as a factor.

For each of the continuous secondary efficacy endpoints, the same ANCOVAfor the primary efficacy endpoint was used, with the respective baseline(−1 hour) value included as the covariate [note that all of thesecondary efficacy endpoints were in relation to baseline (−1 hour),whereas the primary efficacy endpoint was in relation to max (0minute)]. Each ANCOVA was performed using the FAS with subjects includedin their randomized treatment sequence regardless of the treatmentsequence they actually received. Only observed case data was used; thatis, missing values for post-randomization assessments was not imputed.The output from each ANCOVA included the LSM and SE for both treatmentgroups, along with the placebo-corrected LSM, its 95% CI and associatedp-value.

For each of the secondary endpoints related to percent of subjectsachieving certain criteria, the analysis was performed using PROC GENMODwith a logit link (generalized linear model), in order to account forthe crossover design. The analysis included treatment sequence, subjectwithin treatment sequence, period, treatment, mydriatic agent and therespective baseline, as with the ANCOVA for the continuous endpoints.For each analysis, the percentage of subjects in each treatment groupmeeting the criteria, the odds ratio (OR) with 95% CI and p-value wasprovided. For these endpoints, the FAS was used with subjects includedin their randomized treatment sequence regardless of the treatmentsequence they actually received.

In addition, each secondary efficacy endpoint was analyzed by mydriaticagent using the same model indicated above but without mydriatic agentas a factor.

Analysis of Safety

Assessment of safety was evaluated by:

-   -   Conjunctival hyperemia measured with a CCLRU card 4-point scale.        -   None (0)=Normal Appeared white with a small number of            conjunctival blood vessel easily observed.        -   Mild (+1)=Prominent, pinkish-red color of both the bulbar            and palpebral conjunctiva.        -   Moderate (+2)=Bright, scarlet red color of the bulbar and            palpebral conjunctiva.        -   Severe (+3)=Beefy red with petechiae, dark red bulbar and            palpebral conjunctiva with evidence of subconjunctival            hemorrhage.    -   Subjective ocular tolerability measured on a 4-point scale.        -   0—No discomfort        -   1—Mild discomfort        -   2—Moderate discomfort        -   3—Severe discomfort    -   Intraocular pressure (IOP).    -   Heart Rate (HR) and blood pressure (BP).    -   Adverse events.

An adverse event (AE) was any untoward medical occurrence in a patientor clinical study subject administered a study medication(pharmacological/biological product) that did not necessarily have acausal relationship to this medication. An AE could therefore have beenany unfavorable and unintended sign (including abnormal laboratoryfindings), symptom, or disease temporarily associated with the use ofthe study medication, whether or not related to the study medication.Study medication included the investigational drug under evaluation andthe comparator product or vehicle placebo that was given or administeredduring any phase of the study.

Medical conditions/diseases present before starting the investigationaltreatment were only considered AEs if they worsened after starting theinvestigational treatment. Abnormal test results constituted AEs only ifthey induced clinical signs or symptoms, were considered clinicallysignificant, or required therapy.

Severity of an AE was defined as a qualitative assessment of the levelof discomfort of an AE as determined by the Investigator or reported tohim/her by the subject. The assessment of severity was made irrespectiveof study medication relationship or seriousness of the event and was tohave been evaluated according to the following scale:

-   -   1=Mild: present, but not distressing, and no disruption of        normal daily activity.    -   2=Moderate: discomfort sufficient to reduce or affect normal        daily activity.    -   3=Severe: incapacitating, with inability to work or perform        normal daily activity.

A change in severity for a reported AE required an end date for theprevious severity and a new start and end date for the new severity. Forexample, a change in severity could go from mild to severe or fromsevere to moderate. In either case the start or end dates were to havebeen recorded.

Part II—Results

Data on the observed reduction in pupil diameter is provided in Tables1A-1F, 2A-2L, and 3A-3C below. Data characterizing subjects according tochange in accommodation is provided in Tables 4A and 4B. Analysis wasperformed for all subjects and subjects receiving tropicamide (wheredecreased accommodation was considered likely), but not forphenylephrine (where decreased accommodation was considered unlikely).Data characterizing observed eye redness (conjunctival hyperemia) isprovided in Tables 5A through 5E. No subjects in this study requestedadministration of LUMIFY® (ophthalmic solution containing brimonidinetartrate (0.025% w/w) marketed by Bausch & Lomb, Inc.).

TABLE 1A Pupil Diameter by Time Point (Full Analysis Set) 1% w/wPhentolamine 1% w/w Phentolamine Mesylate Ophthalmic Eye MesylateOphthalmic Solution vs. Placebo [1] Visit Solution Placebo LS MeanDifference Statistic (N = 31) (N = 31) (95% CI) p-value Study EyeBaseline (−1 hour) n 31 31 Mean (SD) 4.54 (0.785) 4.45 (0.722) Median4.48 4.33 Min, Max 2.8, 6.5 2.9, 6.4 Max Time Point (0 Minutes) n 31 31Mean (SD) 7.20 (1.128) 6.97 (1.304) Median 7.41 7.42 Min, Max 4.3, 8.84.5, 8.7 30 Minutes n 31 31 Mean (SD) 7.13 (1.075) 6.85 (1.265) Median7.26 7.25 Min, Max 4.3, 8.9 4.4, 8.7 Min = Minimum, Max = Maximum, SD =Standard deviation, LS = Least-squares, CI = Confidence interval, SE =Standard error, LOCF = Least observation carried forward. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, treatment and mydriaticagent as fixed effects, subject within treatment sequence as a randomeffect, and max pupil diameter (0 minutes) as the covariate. [2] From atest comparing the individual treatment change from baseline LS mean tozero. [3] The pooled data from the Study Eye and Non-study Eye.

TABLE 1B Pupil Diameter by Time Point (Full Analysis Set) 1% w/wPhentolamine Mesylate Ophthalmic Eye 1% w/w Phentolamine MesylateSolution vs. Placebo [1] Visit Ophthalmic Solution Placebo LS MeanDifference Statistic (N = 31) (N = 31) (95% CI) p-value Study Eye 30Minutes Change from Maximum (0 Minutes) n 31 31 Mean (SD) −0.07 (0.236)−0.12 (0.221) Median −0.11 −0.11 Min, Max −0.5, 0.6 −0.5, 0.5 30 MinutesChange from Maximum (0 0.06 (−0.05, 0.18) 0.2705 Minutes) Mixed Model[1] Least-squares mean (SE) −0.06 (0.039) −0.13 (0.039) p-value [2]0.1169 0.0034 1 hour n 31 31 Mean (SD) 6.43 (1.413) 6.69 (1.358) Median6.95 7.23 Min, Max 3.4, 8.5 4.1, 8.5 Min = Minimum, Max = Maximum, SD =Standard deviation, LS = Least-squares, CI = Confidence interval, SE =Standard error, LOCF = Least observation carried forward. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, treatment and mydriaticagent as fixed effects, subject within treatment sequence as a randomeffect, and max pupil diameter (0 minutes) as the covariate. [2] From atest comparing the individual treatment change from baseline LS mean tozero. [3] The pooled data from the Study Eye and Non-study Eye.

TABLE 1C Pupil Diameter by Time Point (Full Analysis Set) 1% w/wPhentolamine 1% w/w Phentolamine Mesylate Ophthalmic Eye MesylateOphthalmic Solution vs. Placebo [1] Visit Solution Placebo LS MeanDifference Statistic (N = 31) (N = 31) (95% CI) p-value Study Eye 1 hourChange from Maximum (0 Minutes) n 31 31 Mean (SD) −0.77 (0.530) −0.28(0.261) Median −0.65 −0.24 Min, Max −2.1, −0.1 −1.0, 0.2 1 hour Changefrom Maximum (0 Minutes) −0.49 (−0.70, −0.28) <0.0001 Mixed Model [1]Least-squares mean (SE) −0.77 (0.072) −0.29 (0.072) p-value [2] <0.00010.0005 2 hours n 31 31 Mean (SD) 5.50 (1.497) 6.31 (1.274) Median 6.036.84 Min, Max 2.6, 7.6 3.6, 8.3 Min = Minimum, Max = Maximum, SD =Standard deviation, LS = Least-squares, CI = Confidence interval, SE =Standard error, LOCF = Least observation carried forward. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, treatment and mydriaticagent as fixed effects, subject within treatment sequence as a randomeffect, and max pupil diameter (0 minutes) as the covariate. [2] From atest comparing the individual treatment change from baseline LS mean tozero. [3] The pooled data from the Study Eye and Non-study Eye.

TABLE 1D Pupil Diameter by Time Point (Full Analysis Set) 1% w/wPhentolamine 1% w/w Phentolamine Mesylate Ophthalmic Eye MesylateOphthalmic Solution vs. Placebo [1] Visit Solution Placebo LS MeanDifference Statistic (N = 31) (N = 31) (95% CI) p-value Study Eye 2hours Change from Maximum (0 Minutes) n 31 31 Mean (SD) −1.70 (0.867)−0.66 (0.418) Median −1.62 −0.59 Min, Max −4.0, −0.6 −1.6, 0.2 2 hoursChange from Maximum (0 Minutes) −1.00 (−1.31, −0.68) <0.0001 Mixed Model[1] Least-squares mean (SE) −1.69 (0.117) −0.69 (0.117) p-value [2]<0.0001 <0.0001 4 hours n 31 31 Mean (SD) 4.32 (0.994) 5.34 (1.069)Median 4.27 5.25 Min, Max 2.2, 6.0 3.1, 7.6 Min = Minimum, Max =Maximum, SD = Standard deviation, LS = Least-squares, CI = Confidenceinterval, SE = Standard error, LOCF = Least observation carried forward.[1] From a mixed model with change from max pupil diameter (0 minute) asthe dependent variable, treatment sequence, period, treatment andmydriatic agent as fixed effects, subject within treatment sequence as arandom effect, and max pupil diameter (0 minutes) as the covariate. [2]From a test comparing the individual treatment change from baseline LSmean to zero. [3] The pooled data from the Study Eye and Non-study Eye.

TABLE 1E Pupil Diameter by Time Point (Full Analysis Set) 1% w/wPhentolamine 1% w/w Phentolamine Mesylate Ophthalmic Eye MesylateOphthalmic Solution vs. Placebo [1] Visit Solution Placebo LS MeanDifference Statistic (N = 31) (N = 31) (95% CI) p-value Study Eye 4hours Change from Maximum (0 Minutes) n 31 31 Mean (SD) −2.88 (0.999)−1.63 (0.924) Median −2.87 −1.65 Min, Max −4.9, −0.9 −3.4, 0.6 4 hoursChange from −1.13 (−1.40, −0.87) <0.0001 Maximum (0 Minutes) Mixed Model[1] Least-squares mean (SE) −2.83 (0.145) −1.69 (0.146) p-value [2]<0.0001 <0.0001 6 hours n 31 31 Mean (SD)   3.86 (0.748)   4.52 (0.761)Median 4.01 4.36 Min, Max 2.3, 5.6 2.9, 6.4 Min = Minimum, Max =Maximum, SD = Standard deviation, LS = Least-squares, CI = Confidenceinterval, SE = Standard error, LOCF = Least observation carried forward.[1] From a mixed model with change from max pupil diameter (0 minute) asthe dependent variable, treatment sequence, period, treatment andmydriatic agent as fixed effects, subject within treatment sequence as arandom effect, and max pupil diameter (0 minutes) as the covariate. [2]From a test comparing the individual treatment change from baseline LSmean to zero. [3] The pooled data from the Study Eye and Non-study Eye.

TABLE 1F Pupil Diameter by Time Point (Full Analysis Set) 1% w/wPhentolamine 1% w/w Phentolamine Mesylate Ophthalmic Eye MesylateOphthalmic Solution vs. Placebo [1] Visit Solution Placebo LS MeanDifference Statistic (N = 31) (N = 31) (95% CI) p-value Study Eye 6hours Change from Maximum (0 Minutes) n 31 31 Mean (SD) −3.34 (1.155)−2.45 (1.216) Median −3.55 −2.67 Min, Max −5.4, −1.1 −4.5, 0.2 6 hoursChange from −0.70 (−0.95, −0.45) <0.0001 Maximum (0 Minutes) Mixed Model[1] Least-squares mean (SE) −3.24 (0.132) −2.54 (0.133) p-value [2]<0.0001 <0.0001 Min = Minimum, Max = Maximum, SD = Standard deviation,LS = Least-squares, CI = Confidence interval, SE = Standard error, LOCF= Least observation carried forward. [1] From a mixed model with changefrom max pupil diameter (0 minute) as the dependent variable, treatmentsequence, period, treatment and mydriatic agent as fixed effects,subject within treatment sequence as a random effect, and max pupildiameter (0 minutes) as the covariate. [2] From a test comparing theindividual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2A Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Phenylephrine Study Eye Baseline (−1 hour) n 15 15 Mean (SD)4.56 (0.847) 4.32 (0.642) Median 4.50 4.32 Min, Max 3.3, 6.5 3.3, 5.4Max Time Point (0 Minutes) n 15 15 Mean (SD) 6.44 (1.097) 6.06 (1.288)Median 6.21 5.56 Min, Max 4.3, 8.8 4.5, 8.7 30 Minutes n 15 15 Mean (SD)6.46 (1.029) 6.00 (1.288) Median 6.40 5.53 Min, Max 4.3, 8.6 4.4, 8.7Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2B Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Phenylephrine Study Eye 30 Minutes Change from Maximum (0Minutes) n 15 15 Mean (SD) 0.01 (0.278) −0.06 (0.261) Median −0.09 −0.08Min, Max −0.4, 0.6 −0.5, 0.5 30 Minutes Change from 0.09 (−0.13, 0.30)0.3837 Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) 0.02(0.069) −0.07 (0.069) p-value [2] 0.8028 0.3228 1 hour n 15 15 Mean (SD)5.40 (1.257)   5.74 (1.339) Median 5.49 5.56 Min, Max 3.4, 7.7 4.1, 8.5Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2C Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Phenylephrine Study Eye 1 hour Change from Maximum (0 Minutes) n15 15 Mean (SD) −1.04 (0.602) −0.32 (0.326) Median −1.00 −0.24 Min, Max−2.1, −0.2 −1.0, 0.2 1 hour Change from −0.72 (−1.12, −0.32) 0.0021Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −1.04(0.130) −0.32 (0.130) p-value [2] <0.0001 0.0278 2 hours n 15 15 Mean(SD)   4.35 (1.296)   5.40 (1.264) Median 3.85 5.21 Min, Max 2.6, 6.83.6, 8.3 Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2D Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Phenylephrine Study Eye 2 hours Change from Maximum (0 Minutes)n 15 15 Mean (SD) −2.09 (0.972) −0.65 (0.502) Median −1.86 −0.49 Min,Max −4.0, −0.7 −1.6, 0.2 2 hours Change from −1.38 (−1.96, −0.81) 0.0002Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −2.07(0.202) −0.69 (0.202) p-value [2] <0.0001 0.0053 4 hours n 15 15 Mean(SD)   3.84 (1.004)   4.85 (1.154) Median 3.54 4.93 Min, Max 2.2, 5.83.1, 7.6 Min = Minimum, Max = Maximum, SD = Standard deviation,LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2E Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Phenylephrine Study Eye 4 hours Change from Maximum (0 Minutes)n 15 15 Mean (SD) −2.61 (1.138) −1.20 (0.961) Median −2.31 −1.07 Min,Max −4.9, −0.9 −3.4, 0.6 4 hours Change from −1.18 (−1.57, −0.80)<0.0001 Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE)−2.50 (0.238) −1.32 (0.237) p-value [2] <0.0001 0.0001 6 hours n 15 15Mean (SD)   3.78 (0.868)   4.34 (0.687) Median 3.31 4.29 Min, Max 2.3,5.6 3.3, 5.8 Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2F Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Phenylephrine Study Eye 6 hours Change from Maximum (0 Minutes)n 15 15 Mean (SD) −2.66 (1.168) −1.71 (1.229) Median −2.46 −1.45 Min,Max −4.9, -1.1 −4.3, 0.2 6 hours Change from −0.62 (−1.02, −0.21) 0.0059Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −2.50(0.206) −1.88 (0.206) p-value [2] <0.0001 <0.0001 Min = Minimum, Max =Maximum, SD = Standard deviation, LS = Least-squares, CI = Confidenceinterval, SE =Standard error. [1] From a mixed model with change frommax pupil diameter (0 minute) as the dependent variable, treatmentsequence, period, and treatment as fixed effects, subject withintreatment sequence as a random effect, and max pupil diameter (0minutes) as the covariate. [2] From a test comparing the individualtreatment change from baseline LS mean to zero. [3] The pooled data fromthe Study Eye and Non-study Eye.

TABLE 2G Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Tropicamide Study Eye Baseline (−1 hour) n 16 16 Mean (SD) 4.51(0.750) 4.57 (0.790) Median 4.44 4.49 Min, Max 2.8, 6.0 2.9, 6.4 MaxTime Point (0 Minutes) n 16 16 Mean (SD) 7.91 (0.563) 7.83 (0.486)Median 7.82 7.80 Min, Max 6.8, 8.8 7.2, 8.7 30 Minutes n 16 16 Mean (SD)7.76 (0.664) 7.64 (0.504) Median 7.71 7.46 Min, Max 6.3, 8.9 7.0, 8.5Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2H Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Tropicamide Study Eye 30 Minutes Change from Maximum (0 Minutes)n 16 16 Mean (SD) −0.14 (0.163) −0.18 (0.160) Median −0.14 −0.11 Min,Max −0.5, 0.2 −0.5, 0.0 30 Minutes Change from 0.03 (−0.06, 0.13) 0.4461Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −0.14(0.041) −0.18 (0.041) p-value [2] 0.0037 0.0007 1 hour n 16 16 Mean (SD)  7.39 (0.690)   7.58 (0.505) Median 7.32 7.39 Min, Max 5.6, 8.5 7.0,8.4 Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2I Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Tropicamide Study Eye 1 hour Change from Maximum (0 Minutes) n16 16 Mean (SD) −0.51 (0.284) −0.24 (0.185) Median −0.53 −0.23 Min, Max−1.2, −0.1 −0.7, 0.0 1 hour Change from −0.27 (−0.46, −0.08) 0.0080Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −0.52(0.062) −0.24 (0.062) p-value [2] <0.0001 0.0018 2 hours n 16 16 Mean(SD)   6.57 (0.601)   7.17 (0.392) Median 6.62 7.10 Min, Max 5.4, 7.66.6, 8.1 Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2J Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Tropicamide Study Eye 2 hours Change from Maximum (0 Minutes) n16 16 Mean (SD) −1.33 (0.569) −0.66 (0.338) Median −1.01 −0.66 Min, Max−2.3, −0.6 −1.3, -0.2 2 hours Change from −0.64 (−0.91, −0.37) 0.0002Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −1.32(0.107) −0.68 (0.107) p-value [2] <0.0001 <0.0001 4 hours n 16 16 Mean(SD)   4.77 (0.763)   5.81 (0.756) Median 4.74 5.73 Min, Max 3.8, 6.04.2, 6.8 Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2K Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Tropicamide Study Eye 4 hours Change from Maximum (0 Minutes) n16 16 Mean (SD) −3.14 (0.801) −2.02 (0.710) Median −3.01 −2.12 Min, Max−4.7, −1.8 −3.2, −0.6 4 hours Change from −1.08 (−1.48, −0.69) <0.0001Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −3.12(0.183) −2.03 (0.183) p-value [2] <0.0001 <0.0001 6 hours n 16 16 Mean(SD)   3.94 (0.635)   4.68 (0.812) Median 4.04 4.45 Min, Max 2.9, 5.32.9, 6.4 Min = Minimum, Max = Maximum, SD = Standard deviation, LS =Least-squares, CI = Confidence interval, SE = Standard error. [1] From amixed model with change from max pupil diameter (0 minute) as thedependent variable, treatment sequence, period, and treatment as fixedeffects, subject within treatment sequence as a random effect, and maxpupil diameter (0 minutes) as the covariate. [2] From a test comparingthe individual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Non-study Eye.

TABLE 2L Pupil Diameter by Time Point and Mydriatic Agent (Full AnalysisSet) 1% w/w Phentolamine Mydratic Agent 1% w/w Phentolamine MesylateOphthalmic Eye Mesylate Ophthalmic Solution vs. Placebo [1] VisitSolution Placebo LS Mean Difference Statistic (N = 31) (N = 31) (95% CI)p-value Tropicamide Study Eye 6 hours Change from Maximum (0 Minutes) n16 16 Mean (SD) −3.97 (0.714) −3.15 (0.699) Median −3.78 −3.14 Min, Max−5.4, −2.8 −4.5, −1.9 6 hours Change from −0.79 (−1.14, −0.43) 0.0004Maximum (0 Minutes) Mixed Model [1] Least-squares mean (SE) −3.95(0.175) −3.16 (0.175) p-value [2] <0.0001 <0.0001 Min = Minimum, Max =Maximum, SD = Standard deviation, LS = Least-squares, CI = Confidenceinterval, SE = Standard error. [1] From a mixed model with change frommax pupil diameter (0 minute) as the dependent variable, treatmentsequence, period, and treatment as fixed effects, subject withintreatment sequence as a random effect, and max pupil diameter (0minutes) as the covariate. [2] From a test comparing the individualtreatment change from baseline LS mean to zero. [3] The pooled data fromthe Study Eye and Non-study Eye.

TABLE 3A Percent of Subjects Achieving Pupil Diameter No More Than 0.5mm Above Baseline by Time Point (Full Analysis Set) 1% w/w PhentolamineEye Mesylate Ophthalmic Placebo 1% w/w Phentolamine Mesylate VisitSolution (N = 31) (N = 31) Ophthalmic Solution vs. Placebo [1] Categoryn (%) n (%) Odds Ratio (95% CI) p-value Both Eyes [2] 4 hours n 31 31<=0.5 mm above Baseline (−1 hour) 28 (90.3) 14 (45.2) 18.28 (6.92,48.26) <0.0001 CI = Confidence interval. A reduction was determinedusing the change from baseline (−1 hour) in pupil diameter. Percentagesare the number of subjects with no more than 0.5 mm above Baseline (−1hour), divided by the number of subjects with an assessment at the timepoint. [1] From a generalized estimating equations model with a logitlink, with reduction achievement (yes/no) as the dependent variable,treatment sequence, period, treatment, and mydriatic agent as fixedeffects, subject within treatment sequence as a random effect, andbaseline pupil diameter (−1 hour) as the covariate. [2] The pooled datafrom the Study Eye and Non-study Eye.

TABLE 3B Percent of Subjects Achieving Pupil Diameter No More Than 0.5mm Above Baseline by Time Point and Mydriatic Agent (Full Analysis Set)1% w/w 1% w/w Phentolamine Phentolamine Mesylate Mydratic MesylateOphthalmic Agent Ophthalmic Solution vs. Eye Solution Placebo Placebo[1] Visit (N = 31) (N = 31) Odds Ratio Category n (%) n (%) (95% CI)p-value Phenylephrine Both Eyes [2] 2 hours ′″ n 15 15 <=0.5 mm above 12(80.0)  7 (46.7) 5.32 (1.26, 22.52) 0.0231 baseline (−1 hour) CI =Confidence interval. A reduction was determined using the change frombaseline (−1 hour) in pupil diameter. Percentages are the number ofsubjects with no more than 0.5 mm above Baseline (−1 hour), divided bythe number of subjects with an assessment at the time point. [1] From ageneralized estimating equations model with a logit link, with reductionachievement (yes/no) as the dependent variable, treatment sequence,period, and treatment as fixed effects, subject within treatmentsequence as a random effect, and baseline pupil diameter (−1 hour) asthe covariate. [2] The pooled data from the Study Eye and Non-study Eye.

TABLE 3C Percent of Subjects Achieving Pupil Diameter No More Than 0.5mm Above Baseline by Time Point and Mydriatic Agent (Full Analysis Set)1% w/w 1% w/w Phentolamine Mydratic Phentolamine Mesylate Agent MesylateOphthalmic Eye Ophthalmic Solution vs. Visit Solution Placebo Placebo[1] Category (N = 31) (N = 31) Odds Ratio n (%) n (%) (95% CI) p-valueTropicamide Both Eyes [2] 4 hours n 16 16 <=0.5 mm 13 (81.3)  3 (18.8)40.33 (9.23, 176.16) <0.0001 above Baseline (−1 hour) CI = Confidenceinterval. A reduction was determined using the change from baseline (−1hour) in pupil diameter. Percentages are the number of subjects with nomore than 0.5 mm above Baseline (−1 hour), divided by the number ofsubjects with an assessment at the time point. [1] From a generalizedestimating equations model with a logit link, with reduction achievement(yes/no) as the dependent variable, treatment sequence, period, andtreatment as fixed effects, subject within treatment sequence as arandom effect, and baseline pupil diameter (−1 hour) as the covariate.[2] The pooled data from the Study Eye and Non-study Eye.

TABLE 4A Percent of Subjects With Unchanged Accommodation from Baselineby Time Point (Full Analysis Set) 1% w/w 1% w/w PhentolaminePhentolamine Mesylate Mesylate Ophthalmic Ophthalmic Solution vs. EyeSolution Placebo Placebo [1] Visit (N = 31) (N = 31) Odds Ratio Categoryn (%) n (%) (95% CI) p-value Both Eyes [2] 2 hours n 31 31 Unchangedfrom 22 (71.0) 21 (67.7) 2.31 (1.13, 4.73) 0.0223 Baseline (−1 hour)Unchanged accommodation from Baseline (−1 hour) is defined as a changefrom baseline value >= −1, as measured in diopters. CI = Confidenceinterval. Percentages are the number of subjects with unchangedaccommodation divided by the number of subjects with anassessment at thetime point. [1] From a generalized estimating equations model with alogit link, with unchanged accommodation (yes/no) as the dependentvariable, treatmentsequence, period, treatment, and mydratic agent asfixed effects, subject within treatment sequence as a random effect, andbaseline accommodation (−1hour) as the covariate. [2] The pooled datafrom the Study Eye and Non-study Eye.

TABLE 4B Percent of Subjects With Unchanged Accommodation from Baselineby Time Point and Mydriatic Agent (Full Analysis Set) 1% w/w 1% w/wPhentolamine Phentolamine Mesylate Mydratic Mesylate Ophthalmic AgentOphthalmic Solution vs. Eye Solution Placebo Placebo [1] Visit (N = 31)(N = 31) Odds Ratio Category n (%) n (%) (95% CI) p-value TropicamideBoth Eyes [2] 2 hours n 16 16 Unchanged from 10 (62.5)  6 (37.5) 3.63(1.39, 9.47) 0.0084 Baseline (−1 hour) Unchanged accommodation fromBaseline (−1 hour) is defined as a change from baseline value >= −1, asmeasured in diopters. CI = Confidence interval. Percentages are thenumber of subjects with unchanged accommodation divided by the number ofsubjects with anassessment at the time point. [1] From a generalizedestimating equations model with a logit link, with unchangedaccommodation (yes/no) as the dependent variable, treatment sequence,period, and treatment as fixed effects, subject within treatmentsequence as a random effect, and baseline accommodation (−1 hour) as thecovariate. [2] The pooled data from the Study Eye and Non-study Eye.

TABLE 5A Conjunctival Hyperemia (Safety) 1% w/w Phentolamine EyeMesylate Ophthalmic Placebo Total Timepoint Solution (N = 32) (N = 32)Category (N = 31) n (%) n (%) n (%) Study Eye Baseline (−1 hour) n 31 3264 None 18 (58.1) 21 (65.6) 40 (62.5) Mild 12 (38.7) 11 (34.4) 23 (35.9)Moderate  1 (3.2)  0  1 (1.6) Severe  0  0  0 Numeric Scale [1] n 31 3264 Mean (SD)  0.5 (0.57)  0.3 (0.48)  0.4 (0.52) Median  0.0  0.0  0.0Min, Max 0, 2 0, 1 0, 2 0 Minutes n 31 32 63 None 25 (80.6) 23 (71.9) 48(76.2) Mild  5 (16.1)  9 (28.1) 14 (22.2) Moderate  1 (3.2)  0  1 (1.6)Severe  0  0  0 Percentages are the number of subjects in each categorydivided by the number of subjects with an examination at the Time Point.[1] Conjunctival redness is graded on a 4-point scale: O = none; l =mild; 2 = moderate; 3 = severe

TABLE 5B Conjunctival Hyperemia (Safety) 1% w/w Phentolamine EyeMesylate Ophthalmic Placebo Total Timepoint Solution (N = 31) (N = 32)(N = 32) Category n (%) n (%) n (%) Study Eye Numeric Scale [1] n 31 3263 Mean (SD)  0.2 (0.50)  0.3 (0.46)  0.3 (0.47) Median  0.0  0.0  0.0Min, Max  0, 2  0, 1  0, 2 30 Minutes n 31 32 63 None  3 (9.7) 19 (59.4)22 (34.9) Mild  9 (29.0) 13 (40.6) 22 (34.9) Moderate 19 (61.3)  0 19(30.2) Severe  0  0  0 Numeric Scale [1] n 31 32 63 Mean (SD)  1.5(0.68)  0.4 (0.50)  1.0 (0.81) Median  2.0  0.0  1.0 Min, Max 0, 2 0, 10, 2 Percentages are the number of subjects in each category divided bythe number of subjects with an examination at the Time Point. [1]Conjunctival redness is graded on a 4-point scale: 0 = none; l = mild; 2= moderate; 3 = severe

TABLE 5C Conjunctival Hyperemia (Safety) 1%w/w Phentolamine Eye MesylateOphthalmic Placebo Total Timepoint Solution (N = 31) (N = 32) (N = 32)Category n (%) n (%) n (%) Study Eye 1 Hour n 31 32 63 None  2 (6.5) 19(59.4) 21 (33.3) Mild 11 (35.5) 12 (37.5) 23 (36.5) Moderate 17 (54.8) 1 (3.1) 18 (28.6) Severe  1 (3.2)  0  1(1.6) Numeric Scale [1] n 31 3263 Mean (SD)  1.5 (0.68)  0.4 (0.56)  1.0 (0.83) Median  2.0  0.0  1.0Min, Max 0, 3 0, 2 0, 3 2 Hour n 31 32 63 None  2 (6.5) 19 (59.4) 21(33.3) Mild 14 (45.2) 12 (37.5) 26 (41.3) Moderate 15 (48.4)  1 (3.1) 16(25.4) Severe  0  0  0 Percentages are the number of subjects in eachcategory divided by the number of subjects with an examination at theTime Point. [1] Conjunctival redness is graded on a 4-point scale: 0 =none; 1 = mild; 2 = moderate; 3 = severe

TABLE 5D Conjunctival Hyperemia (Safety) 1% w/w Phentolamine EyeMesylate Ophthalmic Placebo Total Timepoint Solution (N = 31) (N = 32)(N = 32) Category n (%) n (%) n (%) Study Eye Numeric Scale [1] n 31 3263 Mean (SD)  1.4 (0.62)  0.4 (0.56)  0.9 (0.77) Median  1.0  0.0  1.0Min, Max 0, 2 0, 2 0, 2 4 Hour n 31 32 63 None  3 (9.7) 20 (62.5) 23(36.5) Mild 22 (71.0) 11 (34.4) 33 (52.4) Moderate  6 (19.4)  1 (3.1)  7(11.1) Severe  0  0  0 Numeric Scale [1] n 31 32 63 Mean (SD)  1.1(0.54)  0.4 (0.56)  0.7 (0.65) Median  1.0  0.0  1.0 Min, Max 0, 2 0, 20, 2 Percentages are the number of subjects in each category divided bythe number of subjects with an examination at the Time Point. [1]Conjunctival redness is graded on a 4-point scale: 0 = none; 1 = mild; 2= moderate; 3 = severe

TABLE 5E Conjunctival Hyperemia (Safety) 1% w/w Phentolamine EyeMesylate Ophthalmic Placebo Total Timepoint Solution (N = 31) (N = 32)(N = 32) Category n (%) n (%) n (%) Study Eye 6 Hour n 31 32 63 None 10(32.3) 21 (65.6) 31 (49.2) Mild 17 (54.8) 11 (34.4) 28 (44.4) Moderate 4 (12.9)  0  4 (6.3) Severe  0  0  0 Numeric Scale [1] n 31 32 63 Mean(SD)  0.8 (0.65)  0.3 (0.48)  0.6 (0.61) Median  1.0  0.0  1.0 Min, Max0, 2 0, 1 0, 2 Percentages are the number of subjects in each categorydivided by the number of subjects with an examination at the Time Point.[1] Conjunctival redness is graded on a 4-point scale: 0 = none; 1 =mild; 2 = moderate; 3 = severe

Observed experimental results from the IOP measurements are provided inTables 6 and 7 below.

TABLE 6 1% w/w Phentolamine Mesylate Ophthalmic Solution Average ChangePatient Characteristics* in IOP IOP Average Baseline n from BaselineDiurnal IOP (number Baseline (mmHg)** (mmHg) of eyes) (mmHg) Min Max <2215.2 62 −1.35 −10  3 <20 15.1 60 −1.28 −10  3 <19 14.8 55 −1.09 −7 3 <1814.2 48 −1.06 −7 3 <17 13.5 38 −1.00 −6 2 <16 13 32 −0.75 −4 2 <15 12.324 −1.13 −4 2 <14 11.5 16 −1.44 −4 2 <13 11.2 13 −1.54 −4 2 <12 10.8  9−1.67 −4 2 *Per protocol. **As measured at Week 1 Baseline; changesmeasured at 6-8 hours post dose.

TABLE 7 Placebo Patient Characteristics* Average Average Change in IOPBaseline n IOP Baseline Diurnal IOP (number Baseline (mmHg)** (mmHg) ofeyes) (mmHg) Min Max p value <22 15.2 62 −0.65 −6 3 0.0803 <20 15.1 60−0.50 −5 3 0.047  <19 14.8 55 −0.40 −5 3 0.0767 <18 14.2 48 −0.25 −5 30.0471 <17 13.5 38 −0.18 −5 3 0.0734 <16 13   32 0.00 −5 3 0.1276 <1512.3 24 −0.13 −5 3 0.1078 <14 11.5 16 0.06 −4 3 0.0446 <13 11.2 13 0.38−4 3 0.0094 <12 10.8  9 0.56 −1 3 0.0119 *Per protocol. **As measured atWeek 1 Baseline; changes measured at 6-8 hours post dose.

Example 4-Improvement in Near Vision Acuity Using Phentolamine Mesylatein Human Subjects with Open-Angle Glaucoma or Ocular Hypertension

Ability of phentolamine mesylate to improve near vision acuity in humansubjects with bilateral open-angle glaucoma (OAG) or ocular hypertension(OHT) was evaluated according to a clinical study in which an aqueousophthalmic solution containing phentolamine mesylate was administered tothe eye of a patient, and then the patient was evaluated for improvementin near vision acuity in the eye that received the aqueous ophthalmicsolution containing phentolamine mesylate. Approximately 40 subjectswith either OAG or OHT were randomized, for a target of 36 completedsubjects. Subjects were randomized in a 1:1 ratio to receive 1% w/wPhentolamine Mesylate Ophthalmic Solution or placebo once daily for 14days beginning at 8 PM to 10 PM on Day 1 and continuing through Day 14.Evaluations of near vision acuity took place at the Baseline and theTreatment-study Visit days (Day 8±1 Day and Day 15±1 Day) at 8 AM, 10AM, and 4 PM. There were Follow-up Visits on Day 16 at 8 AM±15 minutesand by phone on Day 22 (7 days after the last Treatment-study Visit).Further experimental procedures and results are described below.

Part I—Experimental Procedures

The total length of subject participation was approximately 7 to 8 weekswith six clinic visits and one telephone call follow up, as summarizedbelow:

-   -   Screening Visit (1 day).    -   Washout Visit/period (as necessary) (4-5 weeks with safety check        visit at 2 weeks).    -   Qualification/Baseline Visit (1 day).    -   Treatment-study Visit Day 8 (1 week).    -   Treatment-study Visit Day 15 (1 week).    -   Follow-up clinic Visit on Day 16 (1 day).    -   Follow-up telephone call at Day 22 (1 week).

Human subjects were screened for potential enrollment and, if qualified,enrolled in the study. Inclusion criteria and exclusion criteria for thestudy are set forth below. Human subjects could qualify in either eye.

Inclusion Criteria

-   -   18 years of age or greater.    -   Diagnosis of OAG or OHT. The diagnosis of OHT must have been in        both eyes. For OAG, the diagnosis could have been in either eye        with OHT in the fellow eye. A reported history of untreated OHT        with IOP≥22 mmHg and ≤30 mmHg was preferred.    -   Untreated or treated OAG/OHT with 2 or fewer ocular hypotensive        medications.    -   Untreated (post-washout) mean IOP≥22 mmHg and ≤30 mmHg in the        study eye at the Qualification Visit (8 AM).    -   Corrected visual acuity in each eye+1.0 logMAR or better by        Early Treatment Diabetic Retinopathy Study (ETDRS) in each eye        (equivalent to 20/200 or better) at the Screening Visit and        Qualification Visit.    -   Otherwise healthy and well-controlled subjects.    -   Able and willing to give signed informed consent and follow        study instructions.    -   Able to self-administer study medication or to have study        medication administered by a caregiver throughout the study        period.

Exclusion Criteria

-   -   Closed or very narrow angles (Grade 0-1, Shaffer) or angles that        the investigator judges as occludable and/or with evidence of        peripheral anterior synechiae (PAS)≥180 degrees by gonioscopy        within 6 months prior to Screening Visit in either eye.    -   Glaucoma: pseudo-exfoliation or pigment dispersion component,        history of angle closure or narrow angles. Note: Previous laser        peripheral iridotomy was not allowed.    -   Known hypersensitivity to any a-adrenoceptor antagonists.    -   Previous laser and/or non-laser glaucoma surgery or procedure in        either eye.    -   Refractive surgery in either eye (e.g., radial keratotomy,        photorefractive keratectomy (PRK), laser-assisted in situ        keratomileusis (LASIK), or corneal cross linking).    -   Ocular trauma in either eye within the 6 months prior to        Screening, or ocular surgery or non-refractive laser treatment        within the 3 months prior to Screening.    -   Recent or current evidence of ocular infection or inflammation        in either eye. Current evidence of clinically significant        blepharitis, conjunctivitis, or a history of herpes simplex or        herpes zoster keratitis at Screening in either eye.    -   Ocular medication in either eye of any kind within 30 days of        Screening, with the exception of a) ocular hypotensive        medications (which had to be washed out), b) lid scrubs (which        could be used prior to Screening but could not be used after        Screening) or c) lubricating drops for dry eye        (preservative-free artificial tears), which could be used        throughout the study.    -   Clinically significant ocular disease in either eye as deemed by        the investigator (e.g., corneal edema, uveitis, or severe        keratoconjunctivitis sicca) that might interfere with the study,        including glaucomatous damage so severe that washout of ocular        hypotensive medications for 1 month was not judged safe (i.e.,        cup-to-disc ratio >0.8, severe visual field defect).    -   History of diabetic retinopathy.    -   Contact lens wear within 3 days prior to and for the duration of        the study.    -   Central corneal thickness in either eye >600 m at Screening.    -   Any abnormality in either eye preventing reliable applanation        tonometry (e.g., central corneal scarring).    -   Known hypersensitivity or contraindication to a- and/or        3-adrenoceptor antagonists (e.g., chronic obstructive pulmonary        disease or bronchial asthma; abnormally low blood pressure or        heart rate; second or third degree heart block or congestive        heart failure; or severe diabetes).    -   Clinically significant systemic disease (e.g., uncontrolled        diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine        or cardiovascular disorders) that might interfere with the        study.    -   Participation in any investigational study within 30 days prior        to Screening.    -   Use of any topical or systemic adrenergic or cholinergic drugs        up to 30 days prior to Screening, or during the study unless the        drug, dose and regimen had been consistent for the 30 days prior        to Screening.    -   Changes in systemic medication that could have an effect on IOP        within 30 days prior to Screening or anticipated during the        study.    -   Women of childbearing potential who were pregnant, nursing,        planning a pregnancy, or not using a medically acceptable form        of birth control. An adult woman was considered to be of        childbearing potential unless she was 1 year postmenopausal or 3        months post-surgical sterilization. All females of childbearing        potential must have had a negative urine pregnancy test result        at the Screening and Qualification examinations and must have        intended to not become pregnant during the study.    -   Resting heart rate (HR) outside the normal range (50-110 beats        per minute) at the Screening or Qualification Visit. HR could be        repeated only once if outside the normal range, following at        least a 5 minute rest period in the sitting position.    -   Hypertension with resting diastolic blood pressure (BP)>105 mmHg        or systolic BP>160 mmHg at the Screening or Qualification Visit.        BP could be repeated only once if outside the specified range,        following at least a 5 minute rest period in the sitting        position.

Subjects with an ophthalmic history of increased IOP (≥22 mmHg and ≤30mmHg) were selected for study participation and were screened for studyeligibility.

After Screening, eligible subjects, if being treated at the time withglaucoma medications, were required to washout and refrain fromadministration of any glaucoma drugs for at least 28 days and no morethan 35 days prior to the Qualification Visit. The washout subjects werebrought back at approximately two weeks after starting the washoutperiod for an IOP safety check. In the judgement of the investigator, ifthere was any risk to the eye(s) of the subject, or if the mean IOP ineither eye during washout was >30 mmHg, then an appropriate rescue orprior medication was administered, and the subject was considered ascreen failure. Adverse events occurring during the washout period werealso assessed at this visit. After the washout, where applicable, aQualification Visit occurred before dosing on Day 1.

Subjects not previously treated with any glaucoma drugs did not requirea washout period and could return the following day, or up to 35 dayslater, for their Qualification/Baseline Visit.

At the Qualification/Baseline Visit:

-   -   Females of childbearing potential took a urine pregnancy test at        8 AM.    -   Review of concomitant medications was conducted at 8 AM.    -   Pupil diameter, using a Neuroptics pupillometer, near visual        acuity using a standard chart held at 14 inches, and distance        visual acuity with ETDRS were measured at 8 AM.    -   Eye redness (conjunctival hyperemia) was visually checked at 8        AM, 10 AM and 4 PM using the CCLRU bulbar redness scale.    -   Adverse events were reviewed at each timepoint.

The first dose of study medication was taken at 8 PM to 10 PM on theBaseline Visit (Day 1). Site personnel demonstrated the properinstillation technique to the subject at the Qualification/BaselineVisit (Day 1) and the subject self-administered a dose of artificialtears at the study site, instilling 1 drop in each eye from theunit-dose bottle (Note: If a drop was not instilled into the eye, thesubject was instructed to wait approximately 10-15 seconds andadminister a second drop). The subject received the followinginstructions regarding proper instillation technique:

-   -   The subject should be in a seated position and should tilt his        or her head backward for administration of the study medication.        The bottle of study medication should be held at an almost        vertical position above the eye while the lower eyelid is pulled        down gently, and 1 drop is placed into the conjunctival        cul-de-sac. The tip of the bottle should not touch the eye.        After a drop is instilled in each eye, the subject should keep        the eyes gently closed for approximately 30 seconds. After        successful instillation of the drop in each eye, the subject        should carefully empty any remaining contents as directed.

The subject was given their study medication dropper bottles,instructions when to administer the eye drop (8 PM to 10 PM), and whento return to the clinic.

The subject was instructed to administer one drop to each eye from a newsingle unit-dose bottle, each evening of dosing, and close the eyesgently for 30 seconds, then empty the remaining bottle contents (andstore the opened bottle in the baggie provided and place it in themedication box for return to the study site at the Day 8 Visit). Thesubject was instructed to follow the same procedures each subsequentevening of dosing (approximately 24 hours between doses). At the Day 8visit, the medication box, complete with opened bottles and any unopenedstudy medication was to be returned to the study site where the baggiesof opened medication were removed, and the study medication box wasre-dispensed with the unopened medication. During the second week oftreatment, subjects were instructed to continue to administer one dropof study medication to each eye every night using a new bottle for eachdose, then emptying the remaining contents of that bottle (and storingthe opened bottles in the baggies and placing them back in the box toreturn to the study site at the Day 15 Visit). The Day 15 visit was thelast day of study treatment; no further study medication was dispensedat that visit.

The subject was instructed to contact the investigator should adverseevents of concern occur (e.g., shortness of breath, fainting, etc.), orto go to the emergency room if the event was life-threatening.

Treatment-study visits occurred twice—on Day 8+1 Day and Day 15+1 Day.On Study Day 8, the following was performed:

-   -   Review of concomitant medications was conducted at 8 AM.    -   Near and distance visual acuity were measured.    -   Eye redness (conjunctival hyperemia) was visually checked using        the CCLRU bulbar redness scale.

On Study Day 15, the following was performed:

-   -   Subjects were to bring their used dropper bottles and any unused        medications with them for purposes of drug accountability.    -   Subjects were asked if they had any problems with their eyes        from the last visit, and if there have been any changes in their        medical condition, or concomitant medications, since their last        visit. Any changes in the condition of the subject were recorded        as an adverse event.    -   Near and distance visual acuity distance visual acuity was        measured.    -   Eye redness (conjunctival hyperemia) was visually checked at        each time point using the CCLRU bulbar redness scale.    -   Adverse events were reviewed at each time point.    -   Distance and near visual acuity, pupil diameter, and a complete        ophthalmic examination, including biomicroscopy were also        performed at 4 PM.    -   Subjects completing their Day 15 Visit were instructed not to        resume their original glaucoma medication(s) until after        completion of the Day 22 Follow-up phone call.

A Follow-up Visit occurred at 8 AM±15 minutes on Day 16. Assessmentsperformed at this visit included an IOP measurement at 8 AM±15 minutes,visual acuity, pupil diameter, and safety measures. More specifically,the following were performed:

-   -   Subjects were asked if they had any problems with their eyes        from the last visit, and if there have been any changes in their        medical condition, or concomitant medications, since their last        visit. Any changes in the condition of the subject were recorded        as an adverse event.    -   Review of concomitant medications was conducted at 8 AM.    -   IOP was measured twice in the study eye at 8 AM±15 minutes, and        the two values were averaged. If the difference in the two IOP        measurements was >5 mmHg, a third measurement was obtained, and        the three values were averaged.    -   Pupil diameter, near and distance visual acuity distance visual        acuity, resting HR and BP were measured at 8 AM. Blood pressure,        using the same arm, same cuff size appropriate for arm        circumference throughout the study, and heart rate were measured        after at least 3 minutes rest in the sitting position. If HR or        BP were outside the normal range (HR<50 or >110 beats per        minute, resting diastolic blood pressure (BP)>105 mmHg or        systolic BP>160 mmHg), they could be repeated only once        following at least a 5 minute rest period in the sitting        position.    -   Eye redness (conjunctival hyperemia) was visually checked at        each timepoint using the CCLRU bulbar redness scale.    -   Adverse events were reviewed at 8 AM.    -   Subjects completing their Day 16 Visit were reminded not to        resume their original glaucoma medication(s) until after        completion of the Day 22 Follow-up phone call.

A Follow-up Visit phone call occurred on Day 22, seven days after thelast dose. Any concomitant medications, subject-reported conjunctivaredness and adverse events (AEs) were collected.

Visits on Day 8 and 15 were allowed to be 1 day early or late. If thevisit was late, the subject was advised to take an additional dose fromone of the 2 spare dropper bottles provided in the study medication boxthe night before the visit. The subject was instructed to then empty theremaining contents and store the opened bottle in the baggie providedand place it in the medication box for return to the study site at theirnext visit. If the Day 15 Visit occurred one day early or late, the Day16 Visit and the Day 22 telephone call were adjusted accordingly.

Any subject was permitted to voluntarily withdraw from the study at anytime without prejudice. A non-completing subject was defined as one whoexited the study by their own volition or at the discretion of theInvestigator and/or the Medical Monitor prior to completing all of thestudy procedures required in the protocol.

Study subjects received study medication as set forth in Table 1according to the Treatment Group to which the subject was assigned.Study medication is listed in Table 2.

TABLE 1 Treatment Groups Treatment Group Study Medication andAdministration Protocol 1 One drop of 1% w/w Phentolamine MesylateOphthalmic Solution in each eye daily at 8 PM to 10 PM for 14 days, fromDay 1 through Day 14 for subjects randomized to active treatment. 2 Onedrop of Placebo Ophthalmic Solution in each eye daily at 8 PM to 10 PMfor 14 days, from Day 1 through Day 14 for subjects randomized toplacebo.

TABLE 2 Study Medication Study Medication Composition of StudyMedication 1% w/w Phentolamine 1% w/w phentolamine mesylate MesylateOphthalmic 4% w/w mannitol Solution 3 mM buffer comprising sodiumacetate and acetic acid water pH in the range 4.8 to 5.0 PlaceboOphthalmic 4% w/w mannitol Solution 3 mM buffer comprising sodiumacetate and acetic acid water pH in the range 4.8 to 5.0

Part II—Results

Baseline visual acuity data collected on subjects prior toadministration of phentolamine mesylate at the beginning of the study isprovide in Tables 1-4. Observed improvement in near vision acuity datais provided in Tables 5 and 6. Results of observations for conjunctivalhyperemia is reported in Tables 7 and 8. The data in Tables 7 and 8 showthat there was no statistically significant difference in observedconjunctival hyperemia between patients that received placebo andpatients that received 1% w/w Phentolamine Mesylate Ophthalmic Solution.Observed changes in pupil diameter are provided in Tables 9A, 9B, 10A,10B, 11A, and 11B.

TABLE 1 Baseline Characteristics (Distance-corrected Near Vision Acuity)1% w/w Phentolamine Mesylate Demographics Ophthalmic and BaselineSolution Placebo Total Characteristics (N = 19) (N = 20) (N = 39)Baseline DCNVA, photopic (OD) n 19 20 39 Mean (SD)  0.29 (0.253)  0.25(0.196)  0.27 (0.224) Median  0.20  0.25  0.20 Min, Max −0.1, 0.8 0, 0.6−0.1, 0.8 Note: Min = Minimum, Max = Maximum, SD = Standard deviation,OD = Right eye; OS = Left eye, BCDVA = Best corrected distance visualacuity, DCNVA = Distance corrected near visual acuity. Percentages arethe number of subjects in the category divided by the number of subjectsrandomized in the group. [1] Subjects are categorized as <25 mmHg iftheir study eye Baseline IOP readings at all timepoints (8 AM, 10 AM,and 4 PM) are <25 mmHg. [2] The pooled data from the Study Eye andFellow Eye.

TABLE 2 1% w/w Phentolamine Mesylate Demographics Ophthalmic andBaseline Solution Placebo Total Characteristics (N = 19) (N = 20) (N =39) Baseline DCNVA, photopic (OS) n 19 20 39 Mean (SD)  0.29 (0.271) 0.21 (0.168)  0.25 (0.225) Median  0.20  0.20  0.20 Min, Max −0.2, 0.80, 0.6 −0.2, 0.8 Baseline DCNVA, photopic (Study Eye) n 19 20 39 Mean(SD)  0.28 (0.257)  0.22 (0.179)  0.25 (0.220) Median  0.20  0.20  0.20Min, Max −0.1, 0.7 0, 0.6 −0.1, 0.7 Baseline DCNVA, photopic (FellowEye) n 19 20 39 Mean (SD)  0.30 (0.267)  0.24 (0.187)  0.27 (0.229)Median  0.30  0.20  0.20 Min, Max −0.2, 0.8 0, 0.6 −0.2, 0.8 Note: Min =Minimum, Max = Maximum, SD = Standard deviation, OD = Right eye; OS =Left eye, BCDVA = Best corrected distance visual acuity, DCNVA =Distance corrected near visual acuity. Percentages are the number ofsubjects in the category divided by the number of subjects randomized inthe group. [1] Subjects are categorized as <25 mmHg if their study eyeBaseline IOP readings at all timepoints (8 AM, 10 AM, and 4 PM) are <25mmHg. [2] The pooled data from the Study Eye and Fellow Eye.

TABLE 3 1% w/w Phentolamine Mesylate Demographics Ophthalmic andBaseline Solution Placebo Total Characteristics (N = 19) (N = 20) (N =39) Baseline DCNVA, photopic (All Eyes [2]) n 38 40 78 Mean (SD)  0.29(0.258)  0.23 (0.181)  0.26 (0.223) Median  0.20  0.20  0.20 Min, Max−0.2, 0.8 0, 0.6 −0.2, 0.8 Baseline DCNVA, mesopic (OD) n 19 20 39 Mean(SD)  0.37 (0.279)  0.39 (0.211)  0.38 (0.243) Median  0.40  0.40  0.40Min, Max −0.1, 0.9 0, 0.8 −0.1, 0.9 Baseline DCNVA, mesopic (OS) n 19 2039 Mean (SD)  0.38 (0.289)  0.34 (0.211)  0.36 (0.250) Median  0.30 0.35  0.30 Min, Max 0, 0.9 0, 0.8 0, 0.9 Note: Min = Minimum, Max =Maximum, SD = Standard deviation, OD = Right eye; OS = Left eye, BCDVA =Best corrected distance visual acuity, DCNVA = Distance corrected nearvisual acuity. Percentages are the number of subjects in the categorydivided by the number of subjects randomized in the group. [1] Subjectsare categorized <25 mmHg if their study eye Baseline IOP readings at alltimepoints (8 AM, 10 AM, and 4 PM) are <25 mmHg [2] The pooled datacfromthe Study Eye and Fellow Eye.

TABLE 4 1% w/w Phentolamine Mesylate Ophthalmic Demographics SolutionPlacebo Total and Baseline Characteristics (N = 19) (N = 20) (N = 39)Baseline DCNVA, mesopic (Study Eye) n 19 20 39 Mean (SD)  0.38 (0.286) 0.36 (0.211)  0.37 (0.247) Median  0.30  0.40  0.40 Min, Max  0, 0.9 0, 0.8  0, 0.9 Baseline DCNVA, mesopic (Fellow Eye) n 19 20 39 Mean(SD)  0.38 (0.282)  0.37 (0.213)  0.37 (0.246) Median  0.40  0.40  0.40Min, Max −0.1, 0.9  0, 0.8 −0.1, 0.9 Baseline DCNVA, mesopic (All Eyes[2]) n 38 40 78 Mean (SD)  0.38 (0.280)  0.36 (0.210)  0.37 (0.245)Median  0.35  0.40  0.40 Min, Max −0.1, 0.9  0, 0.8 −0.1, 0.9 Note: Min= Minimum, Max = Maximum, SD = Standard deviation, OD = Right eye; OS =Left eye, BCDVA = Best corrected distance visual acuity, DCNVA =Distance corrected near visual acuity. Percentages are the number ofsubjects in the category divided by the number of subjects randomized inthe group. [1] Subjects are categorized as <25 mmHg if their study eyeBaseline IOP readings at all timepoints (8AM, 10AM, and 4PM) are <25mmHg. [2] The pooled data from the Study Eye and Fellow Eye.

TABLE 5 Observed Change in Near Vision Acuity 1% w/w 1% w/w PhentolaminePhentolamine Mesylate Mesylate Ophthalmic Eye Ophthalmic Solution vs.Light Condition Solution Placebo Placebo [2] Visit (N = 19) (N = 20)Odds Ratio Category [1] n (%) n (%) (95% CI) p-value All Eyes [3]Photopic Day 8, 8AM n 19 20 >=1 line 12 (63.2)  5 (25.0) 6.17 (1.81,24.91) 0.0018 >=2 lines  4 (21.1)  3 (15.0) 2.03 (0.37, 14.10)0.5678 >=3 lines  2 (10.5)  1 (5.0) 1.44 (0.05, 112.24) 1.0000 Day 15,8AM n 19 20 >=1 line 13 (68.4)  8 (40.0) 4.13 (1.41, 12.88) 0.0072 >=2lines  4 (21.1)  1 (5.0) 4.73 (0.44, 245.09) 0.3054 >=3 lines  2 (10.5) 0 0.76 (0.04, >999.99) 1.0000 Day 16, 8AM n 19 20 >=1 line 14 (73.7)  9(45.0) 3.72 (1.24, 11.91) 0.0163 >=2 lines  8 (42.1)  2 (10.0) 6.92(1.23, 73.03) 0.0232 >=3 lines  4 (21.1)  1 (5.0) 2.51 (0.15, 150.96)0.8354 CI = Confidence interval. Percentages are the number of subjectsachieving the improvement divided by the number of subjects with anassessment at the timepoint. [1] 1 line = 1.3 LogMAR; 2 lines = 1.2LogMAR; 3 lines = 1.1 LogMAR, etc. [2] From a logistic regression withtreatment as a factor; and Baseline DCNVA as the covariate. [3] Thepooled data from the Study Eye and Fellow Eye. Subjects are counted in acategory if they meet the reduction criterion for at least one eye.

TABLE 6 Observed Change in Near Vision Acuity 1% w/w 1% w/w PhentolaminePhentolamine Mesylate Mesylate Ophthalmic Eye Ophthalmic Solution vs.Light Condition Solution Placebo Placebo [2] Visit (N = 19) (N = 20)Odds Ratio Category [1] n (%) n (%) (95% CI) p-value All Eyes [3]Mesopic Day 8, 8AM n 19 20 >=1 line  9 (47.4)  7 (35.0) 1.71 (0.58,5.14) 0.3967 >=2 lines  3 (15.8)  1 (5.0) 2.92 (0.20, 165.98) 0.6911 >=3lines  0  0 Day 15, 8AM n 19 20 >=1 line 13 (68.4)  7 (35.0) 4.21 (1.43,13.34) 0.0064 >=2 lines  5 (26.3)  4 (20.0) 1.57 (0.38, 6.92) 0.6820 >=3lines  0  0 Day 16, 8AM n 19 20 >=1 line 12 (63.2)  9 (45.0) 2.60 (0.92,7.73) 0.0752 >=2 lines  8 (42.1)  2 (10.0) 4.11 (0.89, 26.28) 0.0750 >=3lines  3 (15.8)  0 4.92 (0.77, >999.99) 0.1627 CI = Confidence interval.Percentages are the number of subjects achieving the improvement dividedby the number of subjects with an assessment at the timepoint. [1] 1line = 1.3 LogMAR; 2 lines = 1.2 LogMAR; 3 lines = 1.1 LogMAR, etc. [2]From a logistic regression with treatment as a factor; and BaselineDCNVA as the covariate. [3] The pooled data from the Study Eye andFellow Eye. Subjects are counted in a category if they meet thereduction criterion for at least one eye.

TABLE 7 Conjunctival Hyperemia Data for the Study Eye 1% w/wPhentolamine Mesylate Ophthalmic p-value from Solution Placebo Fisher'sexact (N = 19) (N = 20) test Day 8, 8am 0.3899 n (%) None  4 (21.1)  7(35.0) Mild 11 (57.9)  9 (45.0) Moderate  2 (10.5)  4 (20.0) Severe  2(10.5)  0 (0.0) Day 8, 10am 0.2651 n (%) None  4 (21.1)  6 (30.0) Mild12 (63.2) 10 (50.0) Moderate  1 (5.3)  4 (20.0) Severe  2 (10.5)  0(0.0) Day 8, 4pm 0.2651 n (%) None  4 (21.1)  6 (30.0) Mild 12 (63.2) 10(50.0) Moderate  1 (5.3)  4 (20.0) Severe  2 (10.5)  0 (0.0) Day 15, 8am0.3476 n (%) None  4 (21.1)  8 (40.0) Mild 10 (52.6)  8 (40.0) Moderate 3 (15.8)  4 (20.0) Severe  2 (10.5)  0 (0.0) Day 15, 10am 0.3995 n (%)None  5 (26.3)  8 (40.0) Mild 10 (52.6)  8 (40.0) Moderate  2 (10.5)  4(20.0) Severe  2 (10.5)  0 (0.0) Day 15, 4pm 1.0000 n (%) None  7 (36.8) 8 (40.0) Mild  9 (47.4)  9 (45.0) Moderate  3 (15.8)  3 (15.0) Severe 0 (0.0)  0 (0.0) Day 16, 8am 1.0000 n (%) None  9 (47.4)  8 (40.0) Mild 8 (42.1)  9 (45.0) Moderate  1 (5.3)  2 (10.0) Severe  1 (5.3)  1 (5.0)

TABLE 8 Conjunctival Hyperemia Data for the Fellow Eye 1% w/wPhentolamine Mesylate Ophthalmic p-value from Solution Placebo Fisher'sexact (N = 19) (N = 20) test Day 8, 8am 0.2401 n (%) None  4 (21.1) 7(35.0) Mild 11 (57.9) 8 (40.0) Moderate  2 (10.5) 5 (25.0) Severe  2(10.5) 0 (0.0) Day 8, 10am 0.1552 n (%) None  4 (21.1) 6 (30.0) Mild 12(63.2) 9 (45.0) Moderate  1 (5.3) 5 (25.0) Severe  2 (10.5) 0 (0.0) Day8, 4pm 0.1552 n (%) None  4 (21.1) 6 (30.0) Mild 12 (63.2) 9 (45.0)Moderate  1 (5.3) 5 (25.0) Severe  2 (10.5) 0 (0.0) Day 15, 8am 0.4029 n(%) None  6 (31.6) 9 (45.0) Mild  9 (47.4) 7 (35.0) Moderate  2 (10.5) 4(20.0) Severe  2 (10.5) 0 (0.0) Day 15, 10am 0.5049 n (%) None  6 (31.6)8 (40.0) Mild  9 (47.4) 8 (40.0) Moderate  2 (10.5) 4 (20.0) Severe  2(10.5) 0 (0.0) Day 15, 4pm 1.0000 n (%) None  7 (36.8) 8 (40.0) Mild  9(47.4) 9 (45.0) Moderate  3 (15.8) 3 (15.0) Severe  0 (0.0) 0 (0.0) Day16, 8am 0.7468 n (%) None 10 (52.6) 8 (40.0) Mild  7 (36.8) 9 (45.0)Moderate  2 (10.5) 3 (15.0) Severe  0 (0.0) 0 (0.0)

TABLE 9A Observed Change in Pupil Diameter Under Photopic Conditions 1%w/w 1% w/w Phentolamine Eye Phentolamine Mesylate Ophthalmic LightCondition Mesylate Solution vs. Placebo [1] Visit Ophthalmic SolutionPlacebo LS Mean Difference Statistic (N = 19) (N = 20) (95% CI) p-valueAll Eyes [3] Photopic Day 15, 8AM n 38 40 Mean (SD)  2.84 (0.485)  3.54(0.809) Median  2.77  3.45 Min, Max  2.2, 4.4  2.5, 6.0 Day 15, 8AMChange from Baseline n 38 40 Mean (SD) −0.72 (0.578) −0.08 (0.544)Median −0.64 −0.12 Min, Max −2.0, 0.5 −1.2, 1.4 Day 15, 8AM Change from−0.66 (−0.87, −0.45) <0.0001 Baseline ANCOVA [1] Least-squares mean (SE)−0.73 (0.076) −0.07 (0.074) p-value [2] <0.0001  0.3515 Min = Minimum,Max = Maximum, SD = Standard deviation, LS = Least-squares, CI =Confidence interval, SE = Standard error [1] From an analysis ofcovariance (ANCOVA) with (percent) change from Baseline in PupilDiameter as the dependent variable; treatment as a factor; and BaselinePupil Diameter as the covariate. [2] From a test comparing theindividual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Fellow Eye.

TABLE 9B Observed Change in Pupil Diameter Under Photopic Conditions 1%w/w 1% w/w Phentolamine Eye Phentolamine Mesylate Ophthalmic LightCondition Mesylate Solution vs. Placebo [1] Visit Ophthalmic SolutionPlacebo LS Mean Difference Statistic (N = 19) (N = 20) (95% CI) p-valueAll Eyes [3] Photopic Day 15, 8AM Percent Change from Baseline n  38  40Mean (SD) −18.79 (13.168)  −0.56 (17.645) Median −19.55  −3.93 Min, Max−40.4, 17.9 −25.9, 70.1 Day 15, 8AM Percent −18.90 (−25.20, −12.60)<0.0001 Change from Baseline ANCOVA [1] Least-squares mean (SE) −19.13(2.262)  −0.23 (2.205) p-value [2]  <0.0001  0.9157 Day 16, 8AM n  38 40 Mean (SD)  2.85 (0.497)  3.70 (0.865) Median  2.84  3.49 Min, Max 2.0, 4.3  2.4, 6.5 Min = Minimum, Max = Maximum, SD = Standarddeviation, LS = Least-squares, CI = Confidence interval, SE = Standarderror [1] From an analysis of covariance (ANCOVA) with (percent) changefrom Baseline in Pupil Diameter as the dependent variable; treatment asa factor; and Baseline Pupil Diameter as the covariate. [2] From a testcomparing the individual treatment change from baseline LS mean to zero.[3] The pooled data from the Study Eye and Fellow Eye.

TABLE 10A Observed Change in Pupil Diameter Under Photopic Conditions 1%w/w 1% w/w Phentolamine Eye Phentolamine Mesylate Ophthalmic LightCondition Mesylate Solution vs. Placebo [1] Visit Ophthalmic SolutionPlacebo LS Mean Difference Statistic (N = 19) (N = 20) (95% CI) p-valueAll Eyes [3] Photopic Day 16, 8AM Change from Baseline n  38  40 Mean(SD)  −0.70 (0.532)  0.08 (0.537) Median  −0.55  0.01 Min, Max  −1.9,0.3  −1.2, 1.4 Day 16, 8AM −0.80 (−1.01, −0.58) <0.0001 Change fromBaseline ANCOVA [1] Least-squares mean (SE)  −0.71 (0.076)  0.09 (0.074)p-value [2]  <0.0001  0.2421 Day 16, 8AM Percent Change from Baseline n 38  40 Mean (SD) −18.47 (12.457)  3.71 (18.135) Median −17.13  0.12Min, Max −38.8, 12.1 −26.1, 66.7 Min = Minimum, Max = Maximum, SD =Standard deviation, LS = Least-squares, CI = Confidence interval, SE =Standard error [1] From an analysis of covariance (ANCOVA) with(percent) change from Baseline in Pupil Diameter as the dependentvariable; treatment as a factor; and Baseline Pupil Diameter as thecovariate. [2] From a test comparing the individual treatment changefrom baseline LS mean to zero. [3] The pooled data from the Study Eyeand Fellow Eye.

TABLE 10B Observed Change in Pupil Diameter Under Photopic Conditions 1%w/w 1% w/w Phentolamine Eye Phentolamine Mesylate Ophthalmic LightCondition Mesylate Solution vs. Placebo [1] Visit Ophthalmic SolutionPlacebo LS Mean Difference Statistic (N = 19) (N = 20) (95% CI) p-valueAll Eyes [3] Photopic Day 16, 8AM Percent −22.79 (−29.25, −16.32)<0.0001 Change from Baseline ANCOVA [1] Least-squares mean (SE) −18.78(2.323) 4.01 (2.264) p-value [2]  <0.0001 0.0807 Min = Minimum, Max =Maximum, SD = Standard deviation, LS = Least-squares, CI = Confidenceinterval, SE = Standard error [1] From an analysis of covariance(ANCOVA) with (percent) change from Baseline in Pupil Diameter as thedependent variable; treatment as a factor; and Baseline Pupil Diameteras the covariate. [2] From a test comparing the individual treatmentchange from baseline LS mean to zero.

TABLE 11A Observed Change in Pupil Diameter Under Mesopic Conditions 1%w/w 1% w/w Phentolamine Eye Phentolamine Mesylate Ophthalmic LightCondition Mesylate Solution vs. Placebo [1] Visit Ophthalmic SolutionPlacebo LS Mean Difference Statistic (N = 19) (N = 20) (95% CI) p-valueAll Eyes [3] Mesopic Day 15, 8AM  −0.89 (−1.15, −0.63) <0.0001 Changefrom Baseline ANCOVA [1] Least-squares mean (SE)  −1.02 (0.094)  −0.14(0.092) p-value [2]  <0.0001  0.1424 Day 15, 8AM Percent Change fromBaseline n  38  40 Mean (SD) −21.65 (11.281)  −2.03 (14.024) Median−20.22  −2.93 Min, Max −38.6, 1.8 −22.5, 48.8 Day 15, 8AM Percent −19.25(−24.93, −13.57) <0.0001 Change from Baseline ANCOVA [1] Least-squaresmean (SE) −21.46 (2.039)  −2.21 (1.988) p-value [2]  <0.0001  0.2707 Min= Minimum, Max = Maximum, SD = Standard deviation, LS = Least-squares,CI = Confidence interval, SE = Standard error [1] From an analysis ofcovariance (ANCOVA) with (percent) change from Baseline in PupilDiameter as the dependent variable; treatment as a factor; and BaselinePupil Diameter as the covariate. [2] From a test comparing theindividual treatment change from baseline LS mean to zero. [3] Thepooled data from the Study Eye and Fellow Eye.

TABLE 11B Observed Change in Pupil Diameter Under Mesopic Conditions 1%w/w 1% w/w Phentolamine Eye Phentolamine Mesylate Ophthalmic LightCondition Mesylate Solution vs. Placebo [1] Visit Ophthalmic SolutionPlacebo LS Mean Difference Statistic (N = 19) (N = 20) (95% CI) p-valueAll Eyes [3] Mesopic Day 16, 8AM Percent Change from Baseline n  38  40Mean (SD) −19.09 (11.478)  −1.59 (13.521) Median −19.10  −2.14 Min, Max−39.0, 1.0 −24.9, 46.8 Day 16, 8AM Percent −17.07 (−22.62, −11.53)<0.0001 Change from Baseline ANCOVA [1] Least-squares mean (SE) −18.87(1.991)  −1.79 (1.941) p-value [2]  <0.0001  0.3581 Min = Minimum, Max =Maximum, SD = Standard deviation, LS = Least-squares, CI = Confidenceinterval, SE = Standard error [1] From an analysis of covariance(ANCOVA) with (percent) change from Baseline in Pupil Diameter as thedependent variable; treatment as a factor; and Baseline Pupil Diameteras the covariate. [2] From a test comparing the individual treatmentchange from baseline LS mean to zero. [3] The pooled data from the StudyEye and Fellow Eye.

Example 5-Evaluating Impact of Tetrahydrozoline on Pupil Reduction byPhentolamine Mesylate in Human Subjects

A double-masked, randomized, 3-arm, parallel design, single dose studycomparing the tolerability and effect of tetrahydrozoline, phentolaminemesylate, or tetrahydrozoline plus phentolamine mesylate on pupil sizefollowing topical administration of the agent(s) to the eye wasconducted. A total of 45 human subjects were randomized into 3 groups(of 15 subjects each) and all subjects were treated sequentially withone drop per eye of two separate solutions.

Group 1 received one drop of ophthalmic tetrahydrozoline (VISINE®) ineach eye followed by one drop of 0.2% (w/v) ophthalmic phentolaminemesylate in GENTEAL™ eye drop solution (i.e., theTetrahydrozoline+Phentolamine Mesylate Group). GENTEAL™ eye dropsolution is a sterile aqueous ophthalmic solution marketed commerciallyby Alcon.

Group 2 received one drop of placebo (GENTEAL® eye drop solution) ineach eye followed by one drop of 0.2% (w/v) ophthalmic phentolaminemesylate in GENTEAL® eye drop solution (i.e., the Phentolamine MesylateGroup). Group 3 received one drop of ophthalmic tetrahydrozoline(VISINE®) in each eye followed by one drop of placebo (GENTEAL® eye dropsolution) (i.e., the Tetrahydrozoline Group). Pupil size was measured.Additionally, eye redness was measured.

Results observed from the study showed that administration of VISINE®(tetrahydrozoline ophthalmic solution) did not reduce the ability of0.2% (w/v) ophthalmic phentolamine mesylate to reduce pupil diameter.Experimental results for pupil diameter are shown in FIG. 2. Resultsobserved from the study also showed that (tetrahydrozoline ophthalmicsolution) reduced eye redness caused by phentolamine mesylate.Experimental results for eye redness are shown in FIG. 3.

Example 6-Evaluating Phentolamine Mesylate for Causing Burning Sensationor Hyperemia Upon Administration to the Eye of Human Subjects

One drop of 1% w/w Phentolamine Mesylate Ophthalmic Solution wasadministered to eye of human subjects. The subjects were asked to reportany sensation of burning or hypermeia. The results observed arepresented in Table 1 below for a study containing 32 patients thatreceived 1% w/w Phentolamine Mesylate Ophthalmic Solution. The one dropof 1% w/w Phentolamine Mesylate Ophthalmic Solution resulted in lessburning sensation and less hyperemia than that reported for REV-EYES®(0.5% w/w dapiprazole hydrochloride ophthalmic solution containingmannitol (2% w/w), sodium chloride, hydroxypropyl methylcellulose (0.4%w/w), edetate sodium (0.01% w/w), sodium phosphate dibasic, sodiumphosphate monobasic, water for injection, and benzalkonium chloride(0.01% w/w) having a pH of approximately 6.6 and an osmolarity ofapproximately 415 mOsm)) in which two drops of REV-EYES® solution wasadministered to the eye of the patient and then after 5 minutes anothertwo drops of REV-EYES® solution was administered to the eye of thepatient.

TABLE 1 Percentage of Percentage of Study No. of Subjects ReportingSubjects Reporting Test Solution No. Subjects Burning SensationHyperemia REV-EYES ® A 40  40% 100% B 40  58% 100% C 38  82%  62% D 31100%  87% 1% w/w 1 32  0%  34% Phentolamine Mesylate Ophthalmic Solution

The composition of 1% w/w Phentolamine Mesylate Ophthalmic Solution isprovided in the table below.

Study Medication Composition of Study Medication 1% w/w Phentolamine 1%w/w phentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3mM buffer comprising sodium acetate and acetic acid water pH in therange 4.8 to 5.0

Example 7—Treatment of Presbyopia by Phentolamine Mesylate in a HumanSubject

Ability of phentolamine mesylate to treat a human subject suffering frompresbyopia was evaluated according to the experimental proceduredescribed below. Observed results are described below.

Part I—Experimental Procedures

Pupil diameter and visual acuity of the subject were determined atbaseline (Time=−5 minutes), then 1% w/w Phentolamine Mesylate OphthalmicSolution was administered to the subject (1 drop in each eye, Time=0minutes). At Time=40 minutes, one drop of 1% pilocarpine HCl OphthalmicSolution was administered only to the subject's left eye.

Pupil diameter and visual acuity were measured under photopic andmesopic conditions at Time=−5 minutes, 15 minutes, 30 minutes, 45minutes, 60 minutes, 75 minutes, and 90 minutes. Pupil diameter wasadditionally measured at Time=14 hours. Pupil diameter was measured withan infrared pupilometer under scotopic conditions (“mesopic pupildiameter”) and photopic conditions (“photopic pupil diameter”). Visualacuity was measured with an ETDRS chart held at 14 inches distance undermesopic conditions with a mesopic filter (“mesopic visual acuity”) andunder photopic conditions without a mesopic filter (“photopic visualacuity”). For reference, the lines on the ETDRS chart are: 20/125,20/100, 20/80, 20/63, 20/50, 20/40, 20/32, 20/25, and 20/20.

The composition of 1% w/w Phentolamine Mesylate Ophthalmic Solution isprovided in the table below.

Study Medication Composition of Study Medication 1% w/w Phentolamine 1%w/w phentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3mM buffer comprising sodium acetate and acetic acid water pH in therange 4.8 to 5.0 1% w/w Pilocarpine 1% w/w pilocarpine hydrochlorideHydrochloride 0.01% benzalkonium chloride Ophthalmic Solution 0.5%hypromellose 2910 boric acid sodium chloride sodium citrate water pH inthe range 3.5 to 5.5

Part II—Results

Pupil diameter and near visual acuity data obtained from the study arepresented in Table 1, below. In each eye, versus baseline, pupildiameter was reduced and near visual acuity was reduced by 1, 2, 3, or 4lines.

TABLE 1 Pupil Diameter and Visual Acuity by Time Point and LightingConditions Right Eye Left Eye Both Eyes Pupil Visual Pupil Visual VisualTime Conditions Diameter Acuity Diameter Acuity Acuity −5 min. photopic4.73 20/63 3.87 20/100 20/50 mesopic 6.31 20/80 6.26 20/125 20/63  0min. Administer 1% w/w Phentolamine Mesylate Ophthalmic Solution 15 min.photopic 3.99 20/80 4.26 20/100 20/40 mesopic 6.1  20/80 6.41 20/12520/63 30 min. photopic 4.07 20/80 4.6  20/100 20/40 mesopic 6.46 20/806.21 20/100 20/63 40 min. Administer 1% Pilocarpine HCI OphthalmicSolution 45 min. photopic 4.57 20/63 4.17 20/63 mesopic 6.36 5.47 60min. photopic 3.81 20/63 3.6  20/63 20/32 mesopic 6.13 20/80 5.72 20/8020/63 75 min. photopic 3.45 20/50 3.05 20/50 20/32 mesopic 5.79 20/505.22 20/80 20/50 90 min. photopic 3.31 20/40 2.73 20/40 20/32 mesopic4.82 6.35 14 hours photopic 3.16 2.84 mesopic 5.78 5.58

Example 8—Treatment of Presbyopia by Phentolamine Mesylate in a HumanSubject

Ability of phentolamine mesylate to treat a human subject suffering frompresbyopia may be evaluated according to a clinical study in which anaqueous ophthalmic solution containing phentolamine mesylate isadministered to the eye of a patient, and then the patient is evaluatedfor improvement in visual performance, including near-visual visualperformance. Experimental procedures and results are described below.

Part I—Experimental Procedures

Human subjects are screened for potential enrollment and, if qualified,enrolled in the study. Exemplary inclusion criteria and exclusioncriteria for the study are set forth below. If a subject does not meetthe inclusion/exclusion criteria but the investigator believes thesubject should be in the study, a deviation may be allowed following adiscussion between the Principal Investigator and Sponsor of the study.

Inclusion Criteria

-   -   Be ≥40 and ≤65 years of age.    -   Have distance-corrected near visual acuity (DCNVA) of 20/50 or        worse in both eyes.    -   Have best corrected distance visual acuity (BCDVA) of 20/20 or        better in both eyes, and currently depend on reading glasses or        bifocals in which the near addition is >+1.00 diopters.    -   Be otherwise healthy and well-controlled subjects.    -   Be able and willing to give signed informed consent and follow        study instructions.    -   Be able to self-administer study medication or to have study        medication administered by a caregiver throughout the study        period.

Exclusion Criteria

Ophthalmic:

-   -   Clinically significant ocular disease as deemed by the        Investigator (e.g., untreated cataract, treated glaucoma,        corneal edema, uveitis, severe keratoconjunctivitis sicca) that        might interfere with the study.    -   Known hypersensitivity to any a-adrenoceptor antagonists or        cholinergic parasympathomimetic agents.    -   Unwilling or unable to discontinue use of contact lenses during        treatment period.    -   Ocular trauma, ocular surgery (e.g. IOLs) or laser procedure        (e.g. LASIK, PRK) within 5 weeks prior to screening.    -   Recent or current evidence of ocular infection or inflammation        in either eye. Current evidence of clinically significant        blepharitis, conjunctivitis, or a history of herpes simplex or        herpes zoster keratitis at Screening in either eye.    -   Ocular medication in either eye of any kind within 30 days of        Screening, with the exception of a) ocular hypotensive        medications (which must be washed out according to the provided        schedule), b) lid scrubs (which can be used prior to Screening        but cannot be used after Screening) or c) lubricating drops for        dry eye (artificial tears), which can be used throughout the        study.

Systemic:

-   -   Known hypersensitivity or contraindication to α- and/or        β-adrenoceptor antagonists (e.g., chronic obstructive pulmonary        disease or bronchial asthma; abnormally low blood pressure (BP)        or heart rate (HR); second- or third-degree heart blockage or        Congestive Heart Failure (CHF); severe diabetes).    -   Known hypersensitivity or contraindication to cholinergic        parasympathomimetic agents.    -   Clinically significant systemic disease (e.g., uncontrolled        diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine        or cardiovascular disorders) that might interfere with the        study.    -   Initiation of treatment with, or any changes to the current        dosage, drug or regimen of any topical or systemic adrenergic or        cholinergic drugs up to 7 days prior to screening, or during the        study.    -   Participation in any investigational study within 30 days prior        to screening.    -   Women of childbearing potential who are pregnant, nursing,        planning a pregnancy, or not using a medically acceptable form        of birth control. Acceptable methods include the use of at least        one of the following: intrauterine device (IUD), hormonal (oral,        injection, patch, implant, ring), barrier with spermicide        (condom, diaphragm), or abstinence. An adult woman is considered        to be of childbearing potential unless she is 1 year        postmenopausal or 3 months post-surgical sterilization. All        females of childbearing potential must have a negative urine        pregnancy test result at Visit 1/Screening and Visit 2        examinations and must intend not to become pregnant during the        study.    -   Resting HR outside the normal range (50-110 beats per minute) at        the Screening Visit. HR may be repeated only once if outside the        normal range following at least a 5-minute rest period in the        sitting position.    -   Hypertension with resting diastolic BP>105 mmHg or systolic        BP>160 mmHg at the Screening Visit. BP may be repeated only once        if outside the specified range following at least a 5-minute        rest period in the sitting position.

Human subjects enrolled in the study shall randomized into two (or more)Treatment Groups with a 1:1 randomization. The Treatment Groups willreceive doses of either:

-   -   Placebo Ophthalmic Solution,    -   1% w/w Phentolamine Mesylate Ophthalmic Solution,    -   1.5% w/w Phentolamine Mesylate Ophthalmic Solution,    -   2% w/w Phentolamine Mesylate Ophthalmic Solution,    -   1% w/w Phentolamine Mesylate Ophthalmic Solution and 1%        Pilocarpine HCl Ophthalmic Solution,    -   1% w/w Phentolamine Mesylate Ophthalmic Solution and 0.2% to        0.25% Pilocarpine HCl Ophthalmic Solution, or    -   1% w/w Phentolamine Mesylate Ophthalmic Solution and 0.4% to        0.5% Pilocarpine HCl Ophthalmic Solution.

Preferably, the dose is a single drop of ophthalmic solutionadministered to the subject's eye. Treatment Groups receivingpilocarpine-containing treatments may receive them as aqueous solutionswith or without the addition of a vegetable or mineral oil (e.g. castoroil). Description of certain study medications is provided in thefollowing table.

Study Medication Composition of Study Medication Placebo Ophthalmic 4%w/w mannitol Solution 3 mM buffer comprising sodium acetate and aceticacid water pH in the range 4.8 to 5.0 1% w/w Phentolamine 1% w/wphentolamine mesylate Mesylate Ophthalmic 4% w/w mannitol Solution 3 mMbuffer comprising sodium acetate and acetic acid water pH in the range4.8 to 5.0 1.5% w/w Phentolamine 1.5% w/w phentolamine mesylate MesylateOphthalmic 4% w/w mannitol Solution 3 mM buffer comprising sodiumacetate and acetic acid water pH in the range 4.8 to 5.0 2% w/wPhentolamine 2% w/w phentolamine mesylate Mesylate Ophthalmic 4% w/wmannitol Solution 3 mM buffer comprising sodium acetate and acetic acidwater pH in the range 4.8 to 5.0

Doses of study medication are given once daily for the first week andtwice daily for the second week. Visual performance will be evaluated,which may include analysis of near-vision visual acuity, DistanceCorrected Near Vision Acuity (DCNVA), Uncorrected Near Visual Acuity(UNVA), Uncorrected Intermediate Distance Visual Acuity (UIDVA), BestCorrected Distance Visual Acuity (BCDVA), other types of visual acuitymeasurements, and/or Vision questionnaire.

Measures of performance include change in baseline visual acuity for thestudy eye, the non-study eye, both eyes, and/or binocular. Exampleefficacy endpoints include: proportion of subjects gaining 3 lines ormore in mesopic, high contrast, binocular DCNVA; proportion of subjectswith a greater than or equal to 2-line improvement from Baseline inUNVA; visual function questionnaire responses between treatment groupsat the pre-treatment time point at baseline and various study days; andother vision-performance and safety metrics.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A method of treating presbyopia in a human patient, comprisingtopically administering to an eye of the human patient in need thereof(i) a dosage of about 0.5 mg of phentolamine mesylate and (ii) anadditional agent selected from the group consisting of pilocarpine and apharmaceutically acceptable salt thereof, to thereby treat thepresbyopia, wherein the dosage of phentolamine mesylate is administeredto the eye no more than once per day.
 2. The method of claim 1, whereinthe additional agent is pilocarpine hydrochloride.
 3. The method ofclaim 1, wherein the additional agent is topically administered to theeye of the patient in an amount ranging from about 0.1 mg to about 0.5mg.
 4. The method of claim 2, wherein the additional agent is topicallyadministered to the eye of the patient in an amount ranging from about0.1 mg to about 0.5 mg.
 5. The method of claim 1, wherein the methodprovides a therapeutic effect against presbyopia for a duration of atleast 6 hours.
 6. The method of claim 4, wherein the method provides atherapeutic effect against presbyopia for a duration of at least 6hours.
 7. The method of claim 1, wherein the method provides atherapeutic effect against presbyopia for a duration of at least 12hours.
 8. The method of claim 4, wherein the method provides atherapeutic effect against presbyopia for a duration of at least 12hours.
 9. The method of claim 1, wherein the method results in animprovement in near-vision visual acuity characterized by at least atwo-line improvement in the patient's vision measured using a visionchart.
 10. The method of claim 4, wherein the method results in animprovement in near-vision visual acuity characterized by at least atwo-line improvement in the patient's vision measured using a visionchart.
 11. The method of claim 1, wherein the method results in animprovement in near-vision visual acuity characterized by at least athree-line improvement in the patient's vision measured using a visionchart.
 12. The method of claim 4, wherein the method results in animprovement in near-vision visual acuity characterized by at least athree-line improvement in the patient's vision measured using a visionchart.
 13. The method of claim 1, wherein the patient experiences anincrease in eye redness of no more than one grade measured using theCCLRU Redness Grading Scale compared to the patient's level of eyeredness without receiving said dosage of alpha-adrenergic antagonist.14. The method of claim 4, wherein the patient experiences an increasein eye redness of no more than one grade measured using the CCLRURedness Grading Scale compared to the patient's level of eye rednesswithout receiving said dosage of alpha-adrenergic antagonist.
 15. Themethod of claim 1, wherein the patient experiences at least a 1 mmreduction in pupil diameter when measured under mesopic conditionsrelative to the diameter of the patient's pupil under the same mesopicconditions but not having received said dosage.
 16. The method of claim4, wherein the patient experiences at least a 1 mm reduction in pupildiameter when measured under mesopic conditions relative to the diameterof the patient's pupil under the same mesopic conditions but not havingreceived said dosage.
 17. The method of claim 1, wherein the patientexperiences at least a 1 mm reduction in pupil diameter when measuredunder photopic conditions relative to the diameter of the patient'spupil under the same photopic conditions but not having received saiddosage.
 18. The method of claim 4, wherein the patient experiences atleast a 1 mm reduction in pupil diameter when measured under photopicconditions relative to the diameter of the patient's pupil under thesame photopic conditions but not having received said dosage.
 19. Themethod of claim 1, wherein the patient experiences the effect of havinga pupil diameter of less than 2.6 mm in the eye that received saiddosage when measured under photopic conditions.
 20. The method of claim4, wherein the patient experiences the effect of having a pupil diameterof less than 2.6 mm in the eye that received said dosage when measuredunder photopic conditions.
 21. The method of claim 1, wherein the dosageis administered as an eye drop.
 22. The method of claim 4, wherein thedosage is administered as an eye drop.
 23. The method of claim 1,wherein the dosage is administered at or near the bedtime of thepatient.
 24. The method of claim 4, wherein the dosage is administeredat or near the bedtime of the patient.
 25. The method of claim 23,wherein the additional agent is administered to said eye of the patientafter administering to said eye of the patient the dosage ofphentolamine mesylate.
 26. The method of claim 24, wherein theadditional agent is administered to said eye of the patient afteradministering to said eye of the patient the dosage of phentolaminemesylate.
 27. A method of treating presbyopia in a human patient,comprising topically administering to an eye of the human patient inneed thereof (i) a dosage of phentolamine mesylate in an amount lessthan about 1 mg and (ii) an additional agent selected from the groupconsisting of pilocarpine, aceclidine, brimonidine, and apharmaceutically acceptable salt thereof, to thereby treat thepresbyopia, wherein the dosage of phentolamine mesylate is administeredto the eye no more than once per day.
 28. The method of claim 27 whereinthe additional agent is pilocarpine hydrochloride.
 29. The method ofclaim 28, wherein the additional agent is topically administered to theeye of the patient in an amount ranging from about 0.1 mg to about 0.5mg.
 30. The method of claim 27, wherein the dosage of phentolaminemesylate is about 0.5 mg.